DNA was collected for living participants of the FHSO in the late 1980s and through 1990s. Genotyping of about 1900 offspring subjects was performed under the Cardio-Genomics program that focused on selected candidate genetic markers of cardiovascular development. Two common Arg16Gly and Gln27Glu polymorphisms of the ADRB2 gene were selected for this study because of their documented multiple physiological and health effects that warrant exploration of their relationship with aging-associated phenotypes.

The Glu27Glu homozygous genotype showed a highly significant protective role against cancer (all sites but skin) for men and women combined. The results were evaluated for survival patterns and relative risks focusing on the 4th, 5th, and 6th examinations. The protective effect holds for each sex, and similar relationships were observed for breast and prostate cancers as well as for the remaining cancer sites. The Glu27Glu homozygote is tightly linked to the Gly16Gly homozygote, and the Gly16Gly/Glu27Glu compound genotype resembles the effect of the Glu27Glu genotype. The effects of the Gln27Gln and Gln27Glu genotypes can theoretically be mediated or modulated by the Arg16Gly polymorphism. However, there is no evidence of a functional relationship between the Arg16Gly polymorphism and these aging-associated phenotypes.population. Fig. 4B shows that the Gln27Glu polymorphism affects the signaling properties of the β2-adrenergic receptor and that the Glu27 allele enhances receptor coupling to Gs protein, which activates adenylyl cyclase and leads to increased intracellular cAMP concentration (Green et al., 1994; Liggett, 2003). As a result, the Glu27 allele confers enhanced bronchodilator response to β2-adrenergic agonists (Israel et al., 2000) and reduced risk of asthma exacerbations (Wechsler et al., 2006). However, elevated cAMP concentration may also increase the activity of protein kinase A and downstream signaling pathways that promote cell growth and proliferation (Garcia-Sainz et al., 1997; Rangwala et al., 2000). This effect may contribute to increased risk of cancer at younger ages. At older ages, however, increased cAMP concentration may activate protein kinase A-dependent pathways that promote cell survival and resistance to stressors like oxidative damage (McCubrey et al., 2007; Salmeen et al., 2008). This effect may contribute to improved healthspan and lifespan at older ages.

Overall, our study provides evidence for a systemic role of the ADRB2 gene in healthy aging and longevity, and highlights the importance of considering both disease-specific and overall longevity phenotypes when investigating genetic factors that influence aging-related outcomes. Our findings suggest that the Gln27Glu polymorphism may be a promising target for interventions aimed at promoting healthy aging and extending lifespan. However, further studies are needed to confirm our results and elucidate the underlying mechanisms of its effects.The text contains several errors that need correction. Here is the processed text:

The young-old population (i.e., those who reached the age of 65 years, about 40% of the sample, at the end of follow-up in 2007) showed a pattern similar to that of the entire sample. This implies that evolutionary selection likely worked against the ancestral Glu27 allele and favored the derived Gln27 allele because mortality selection at young ages could not explain the observed proportions given the small death rates of adults (e.g., http://www.cdc.gov/nchs/deaths.htm) and infants (Singh and Yu, 1995) in contemporary U.S. The systemic role of the polymorphism is further augmented by the consistently unfavorable role of the derived Gln27 allele in the etiology of cancer, MI, and IC. The ancestral Glu27 allele seems to play a protective role for these phenotypes. The mode of inheritance for these alleles is different for cancer, MI, and IC. Specifically, Fig. 1AC shows the recessive effect of the Glu27 allele on cancer phenotype, whereas Fig. 1E and F show its dominant effect on MI and on the compound phenotype of MI and IC. Fig. 4B shows that frequencies of the Gln27 and Glu27 alleles are the same in the sample of individuals who died relatively early in life (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 significantly larger than that of the Glu27 allele, whereas frequencies of these alleles become the same in the LL group (Fig. 4D, LS > 83 years). This implies that the frequency of the Gln27 allele increases in 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 dynamic is explained by a survival disadvantage of carriers of the Gln27 allele attributable to increased risks of cancer, MI, and IC, as shown in Fig. 4C for the case of cancer (similar patterns hold when deaths among MI and IC patients 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.