It has been well documented that the longevity trait exhibits sexual dimorphism. Women occupy about 80% of centenarians (Li et al., 2009). In this study, we find that the association of b2AR with human longevity is linked to gender. The two synonymous SNPs of ADRB2 and their haplotypes tend to be associated with the longevity trait preferentially in men. That the MAFs of the two SNPs were enriched with the death ages strongly supports the association. Previously, it has been reported that transgenic mice with cardiac-selective expression of b2AR showed a dramatic reduction in male lifespan, while this phenotype was much less severe in females (Gao et al., 2003; Thireau et al., 2010), supporting the hypothesis that reduced b2AR levels in vivo have a beneficial effect on male lifespan. Perhaps, consistently, it has been reported that male but not female mice lacking the protein kinase A regulatory subunit RIIb have extended lifespan (Enns et al., 2009). The reason why the b-adrenergic system exhibits sexual dimorphism in the control of lifespan is largely unknown. In a transgenic mouse model, it has been shown that orchiectomy rescues this life-threatening phenotype caused by the over-expression of b2AR, suggesting that sex hormones such as testosterone are critical to the underlying mechanism or pathway (Gao et al., 2003; Thireau et al., 2010). On the other hand, the transgenic mice develop heart failure, and therefore, the mechanism by which over-expression of b2AR shortens male lifespan may not reflect the natural process of aging. For this reason, it would be better to compare the longevity of mouse models lacking either b1AR or b2AR because these mice appear normal. The lifespan phenotypes of these mice remain to be reported (Rohrer et al., 1999).

In summary, we show that common haplotypes of b2AR, which affect its translational efficiency, are associated with longevity in men and that the level of b2AR protein is inversely associated with male lifespan. These findings may well have clinical implications for treating patients with bAR agonists or antagonists. On the other hand, it is well known that the evaluation of a long-term effect of a pharmacological intervention in humans is methodologically difficult, as well as being time- and funding- intensive in clinical practice. Our study suggests that the identification of genetic variants that exert similar effects to the pharmacological interven- tions may provide an alternate ‘shortcut’ route to achieving such goals.

Experimental procedures

Human subjects

We performed a 10-year follow-up study for the ‘Chinese Longitudinal Healthy Longevity Survey (CLHLS)’ from 1998 to 2008 (Zeng & Gu, 2008). In the Survey, 9093 oldest-olds aged 80–116 were recruited in 1998 and interviewed in 1998, 2000, 2002, 2005, and 2008 with a questionnaire and basic physical examinations. In 2011, we recruited additional 21 blood samples from the male oldest-old in south of China. An individual’s age reported in the survey was based on the Resident Identity Card of the People’s Republic of China and the Household Register, with additional evidence including genealogical records, marriage certificates, demographic statistical data of local administration offices, migration documents, certification for employment or military service, and the witness of neighbors. The Resident Identity Card and Household Register are both issued by the Ministry of Public Security of the People’s Republic of China to an individual and a family, respectively. The Resident Identity Card has the holder’s name and a number that carries the information on place and date of birth; the Household Register presents the basic information on names, genders, dates of birth, relationship, marriage status, and the professions of all family members.

Indeed, the b-adrenergic system exhibits sexual dimorphism in several aspects, including the expression of bARs (Paulose & Kanungo, 1982), memory impairment (Cahill & Van Stegeren, 2003), growth hormone release (Krieg et al., 1986), vascular constriction (Li & Duckles, 1994), and Ca2+ influx in cardiac myocyte (Vizgirda et al., 2002). Notably, epinephrine-induced cAMP accumulation in hepatocytes is about 3-fold higher in females than in males (Yagami et al., 1990). Growth hormone release from pituitary cells induced by b2-adrenergic stimulation is more potent in male than in female rats (Krieg et al., 1986). The rate of lipolysis stimulated by 8-bromo-cAMP and isoprenaline is greater in the subcutaneous than in omental adipocytes, and this is not seen in males (Lundgren et al., 2008). b1 or b2AR blocking treatment has a cardio- protective effect after high-risk vascular surgery in men but not in women (Matyal et al., 2008). Whether these differences are associated with the sexual dimorphism of b2ARs in the regulation of human lifespan requires further investigation.

We selected 384 centenarians and 384 gender-matched young individuals from northern China as population 1. The population 2 consisted of 579 cases with exceptional long lifespan (age   95-year for men and age   100-year for women) and 644 young individuals from southern China. A detailed protocol diagram for the inclusion of the participants was provided as Fig. S1 (Supporting information). The study protocol was approved by the Institutional Review Board, Institute of Molecular Medicine at Peking University. 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. The study conformed to the principles outlined in the Declaration of Helsinki. (The detailed information on sampling and storage was in ‘Sampling and genotyping’ in Data S1, Supporting information).