Haplotype Frequency (case/control) OR (95% CI) P Perm P C-G 0.523/0.635 0.63 (0.51–0.78) 1.86E-5 A-C 0.332/0.250 1.49 (1.17–1.88) 7.00E-4 C-C 0.133/0.107 1.29 (0.92–1.80) 0.119 0.323

signaling to human lifespan. In addition to interacting with GTP- binding proteins (Gs and Gi) that control the activation of AC, b2AR interacts directly with protein kinase and adaptor proteins to regulate a range of other biological functions raising the possibility that the benefits of reduced b2AR signaling may be multifactorial in nature. (Benovic, 2002). Second, b2AR is an important mediator of lipolysis (Lima et al., 2005) and has been genetically linked to obesity (Masuo et al., 2005) and insulin resistance (Park et al., 2008). Given the tight coupling between longevity and metabolism, it is reasonable to speculate that reduced b2AR activity may improve insulin sensitivity with age and that these metabolic changes may promote longevity. It was well documented that b-adrenergic responses decrease with age (Xiao et al., 1998). While the reasons for this decline are not apparent, it is intriguing to speculate that this is a response to events that occur with age and that individuals with a lower response earlier in life may be protected from changes associated with the aging process.

OR (95% CI), odds ratio with 95% confidence interval; P: P-value from chi-square test; Perm P: P-value for permutation correction.

b1AR and b2AR are two well-studied subtypes of beta adrenoceptors (Xiao et al., 2006). b1AR is predominantly expressed in the heart, cerebral cortex, and kidney, while b2AR appears more abundant in blood vessels, lung, skeletal muscle, and adipose tissue. It has been shown with engineered mouse models that the b1 receptor is critical for the regulation of cardiac inotropy and chronotropy (Rohrer et al., 1996). Both subtypes are important in regulating vascular relaxation, metabolic rate, and diet-induced thermogenesis (Rohrer et al., 1999). In the b- adrenergic signaling system (Fig. S2, Supporting information), the bAR dissociates a Gsa subunit from the Gsa-b-c complex to activate adenylyl cyclase (AC). AC catalyzes the conversion of ATP into cAMP, activating PKA, and subsequently promoting phosphorylation of downstream target proteins such as Raf-1; which leads to its inactivation (Dhillon & Kolch, 2002). Reduced PKA signaling is known to result in enhanced yeast replicative and chronological lifespan (Lin et al., 2002; Gendron et al., 2003), and it was recently documented that mice lacking AC5 have decreased PKA activity, leading to the activation of the Raf/MEK/ ERK signaling pathway and enhanced lifespan in mice (Yan et al., 2007). The prolonged lifespan is presumably due to protecting mice from aging- induced pressure overload and catecholamine-induced stress (Vatner et al., 2009). Despite the fact that no significant associations were found between the ADCY5 or ADCY6 genotype and human longevity in the present study, we demonstrated that b2AR, the upstream activator of AC5 and/or AC6, is strongly associated with longevity in men. Furthermore, we found that the haplotype A-C formed by two SNPs (rs1042718 and rs1042719) reduced the expression of b2AR and was

Finally, certain genetic variants of have been linked to a lower risk of coronary events in elderly population (Heckbert et al., 2003) as well as myocardial infarction (Zee et al., 2005), asthma (Wechsler et al., 2009), hypertension (Ge et al., 2005), and obesity (Masuo et al., 2005). We did not test how genotypes affect disease status in centenarian population. This is due to the fact that the disease status was based on the report, not on medical examination. Interestingly, a recent study has found that a b2AR genetic polymorphism was associated with healthy aging (Kulminski et al., 2010).

One interesting potential molecular link between b2AR activation and aging has emerged from a recent study (Hara et al., 2011), which shows that stimulation of b2ARs in response to chronic stress leads through

it is well documented that women have longer life expectancy than men (Zeng & Vaupel, 2004). It is therefore very difficult to find a large population of male centenarians. A small sample size will increase statistic errors and bias in conclusions, and thus, whether or not b2AR is associated with longevity trait in other ancestries needs to be further investigated. Nonetheless, such data can be used as one of the tests for meta-analysis of human longevity in the future.

PKA and b-arrestin to accelerated DNA damage and destabilization p53 through Akt-mediated Mdm2 activation. Given the support accumulated DNA damage as a driver of aging, it is tempting speculate that one benefit of reduced b2AR signaling involves ation of this response to chronic stress.