Here, we assessed the genetic contribution of bAR signaling system to the human longevity trait in Han Chinese long-lived and younger individuals. The average lifespan in China was 71 and 74 years of age for men and women, respectively. Thus, those who were at the ages of 95 or above were considered as the long-lived, and middle-aged groups were taken as controls. The SNPs selected from ADRB1, ADRB2, ADCY5, ADCY6, and MAPK1 were genotyped and evaluated for their association with the longevity trait. We identified two synonymous SNPs of ADRB2 (rs1042718 and rs1042719) that were significantly associated with longevity in men through dominant and additive models. Despite the fact that no positive signals were observed in women in the allele association study, we noticed that these two SNPs exhibited marginal P-values in genotypic association in women. This may suggest that the effect size in women is smaller than in men. The association with male longevity was replicated in two geographically isolated Han Chinese populations. The MAFs of the two SNPs were increased with the death ages, providing additional support for the association. In further studies, we demonstrated that the haplotype formed by these two SNPs, which increased the probability of becoming a centenarian, also led to decreased protein production of b2AR. In contrast, overproduction of b2AR is associated with decreased male lifespan. The other SNPs analyzed were not found to be associated with human longevity in the studied populations. To our knowledge, this is the first indication that ADRB2 is linked to human longevity and that a suppression of b2AR production may have beneficial effects on lifespan.

Discussion

Longevity is a complex trait affected by both genetic and environmental factors (Herskind et al., 1996; Li et al., 2009; Zeng et al., 2010). A great effort has been made to assess to what extent genetics contributes to the trait over the past decades. For instance, a Danish twin-based study indicated that the heritability of longevity was about 0.33 and 0.44 for men and women, respectively (Herskind et al., 1996). A recent meta-analysis of four GWAS identified 273 SNPs associated with longevity at low P-values (< 0.0001) (Newman et al., 2010).

A C G C G (A) (B) GG A A C 400 P = 0.002 ADRB2 350 3 4 7 8 9 300 1 1 1 1 1 7 7 7 7 7 2 2 2 2 2 4 4 4 4 4 250 0 0 0 0 0 1 1 1 1s s s s s r r r r r200 A C G C G150 a CMV ADRB2 Flu C C100 b CMV ADRB2 Flu50 A C c CMV ADRB2 Flu0 d CMV Flu Haplotype C-G C-C A-C e TK Rlu Frequency (%)52.3/63.5 13.correctly spelled and no further changes are needed. 

The sentence "PKA and b-arrestin to accelerated DNA damage and destabilization p53 through Akt-mediated Mdm2 activation" has a grammatical error. It should be corrected to "PKA and b-arrestin accelerate DNA damage and destabilize p53 through Akt-mediated Mdm2 activation."

The sentence "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" has a word that needs to be split. It should be corrected to "Given the support accumulated DNA damage as a driver of aging, it is tempting to speculate that one benefit of reduced b2AR signaling involves attenuation of this response to chronic stress."

The sentence "The two synonymous SNPs of ADRB2 and their haplotypes tend to be associated with the longevity trait preferentially in men" has a grammatical error. It should be corrected to "The two synonymous SNPs of ADRB2 and their haplotypes tend to be preferentially associated with the longevity trait in men."

The sentence "Perhaps, consistently, it has been reported that male but not female mice lacking the protein kinase A regulatory subunit RIIb have extended lifespan" has an unnecessary word. It should be corrected to "Consistently, it has been reported that male mice lacking the protein kinase A regulatory subunit RIIb have extended lifespan, while female mice do not (Enns et al., 2009)."

The sentence "Whether these differences are associated with the sexual dimorphism of b2ARs in the regulation of human lifespan requires further investigation" has an extra letter. It should be corrected to "Whether these differences are associated with the sexual dimorphism of b2AR in the regulation of human lifespan requires further investigation."

The sentence "The study protocol was approved by the Institutional Review Board, Institute of Molecular Medicine at Peking University" has a minor grammatical error. It should be corrected to "The study protocol was approved by the Institutional Review Board of the Institute of Molecular Medicine at Peking University."

The sentence "The signed informed consent forms were obtained from all participants or their represen- tative family members in cases of the oldest-olds who were incapable of signing" has an unnecessary space. It should be corrected to "The signed informed consent forms were obtained from all participants or their representative family members in cases of the oldest-olds who were incapable of signing."

All other sentences are correctly spelled and grammatically sound.The text seems to be a list of references and a description of statistical analysis. As such, there is no need for major corrections to the content. However, there are some minor errors in spelling, grammar, and formatting that need to be addressed.

Processed Text:

Used to avoid any possible interference, translational efficiency was measured by firefly luciferase activity. Transfection efficiency was standardized by reference to Renilla luciferase activity resulting from the parallel introduction of this plasmid into the test cells.

References:

Benovic JL (2002) Novel beta2-adrenergic receptor signaling pathways. J. Allergy Clin. Immunol. 110, S229-S235.