Contents lists are available at the ScienceDirect Mechanisms of Ageing and Development journal homepage: www.elsevier.com/locate/mechagedev. The beta2-adrenergic receptor (ADRB2) gene's Gln27Glu polymorphism, but not the Arg16Gly polymorphism, appears to be related to a wide range of phenotypes associated with aging. These include cancers at different sites, myocardial infarction (MI), intermittent claudication (IC), and overall/healthy longevity in the Framingham Heart Study Offspring cohort. The Gln27Gln genotype increases the risks of cancer, MI, and IC, while the Glu27 allele or, equivalently, the Gly16Glu27 haplotype tends to protect against these diseases. Genetic associations with longevity are of the opposite nature at young-old and oldest-old ages, highlighting the phenomenon of antagonistic pleiotropy. The mechanism of antagonistic pleiotropy is associated with an evolutionary-driven advantage of carriers of a derived Gln27 allele at younger ages and their survival disadvantage at older ages as a result of increased risks of cancer, MI, and IC. The ADRB2 gene can play an important systemic role in healthy aging in an evolutionary context that warrants exploration in other populations. 2010 Elsevier Ireland Ltd. All rights reserved.

The ADRB2 gene is involved not only in vascular responses but also in pulmonary, endocrine, and central nervous systems functioning (Brodde, 2008a,b). Arg16Gly and Gln27Glu polymorphisms' roles in the pathophysiology of heart disease (Heckbert et al., 2003), hypertension (Puddu et al., 2007), obesity (Jalba et al., 2008), diabetes (Pinelli et al., 2006), asthma (Contopoulos-Ioannidis et al., 2005), Alzheimer's disease (Yu et al., 2008), COPD (Matheson et al., 2006), and cancer (Huang et al., 2001) have been studied in different populations.

Introduction: The etiology of complex phenotypes entails epistatic and gene-environment interactions, making relevant gene association studies a challenging task. Polymorphisms in the beta2-adrenergic receptor (ADRB2) gene have long attracted the attention of health researchers for their possible multiple physiological and health effects, particularly those involving vascular responses and airway function (Buscher et al., 1999; Contopoulos-Ioannidis et al., 2005; Hindorff et al., 2005; Snyder et al., 2005). ADRB2 is a member of the receptor family that mediates the physiological effects of the hormone epinephrine and the neurotransmitter norepinephrine. Adrenergic stimulation of the ADRB2 influences cardiovascular function by regulating vasomotor tone (Guimaraes and Moura, 2001). This function makes ADRB2 an important target in cardiovascular disease therapy. The two most common functional single nucleotide polymorphisms of the ADRB2 gene are rs1042713 (46GA) and rs1042714 (79CG), which result in changes of amino acids at codon 16, Arg to Gly, and at codon 27, Gln to Glu, respectively (George, 2008). Various studies have shown that the role of these polymorphisms is broad in nature because of their involvement not only in vascular responses but also in pulmonary, endocrine, and central nervous systems functioning.

The pleiotropy of the effects of these genetic variants makes them promising candidates for studies of genetic predisposition to healthy aging (Melzer et al., 2007), which is often defined as life with preserved health and physical, social and mental wellness, independence, and quality of life (Peel et al., 2004). Although a common goal is to determine genetic pathways that could directly modulate senescence (Johnson, 2005), a more realistic strategy is to understand mechanisms involved in the process of development of aging-associated disorders to improve the health of an increasing elderly population in contemporary societies (Hadley and Rossi, 2005; Melzer et al., 2007; Olshansky et al., 2007; Sierra et al., 2008). Currently, a large number of genetic studies focus on aging per se in model organisms and humans (Vijg and Suh, 2005). Likewise, a large body of studies focus on a single particular disease phenotype (e.g., Brodde, 2008b). Integration of these diverse initiatives in a systematic way could greatly advance studies of the genetics of healthy aging. The problem is that an integrative approach requires rich data on health and longevity, which are typicallyeffect is attributed to the Gln27 allele. The study categorized BMI using the U.S. federal guidelines, and diabetes was defined based on the WHO-1985 guidelines. The FHSO cohort included respondents aged 570 years residing in Framingham, MA, launched in 19711975, resulting in a total sample of N = 5124 subjects. The publicly released limited-access FHSO data available for this study have phenotypic information assessed at six FHSO examinations performed between 1971 and 1997. The study participants have been followed for the occurrence of certain aging-associated diseases, with emphasis on CVDs and cancer, and death through 2007. Our analyses show that the Gln27Glu polymorphism is more relevant to diseases than the Arg16Gly polymorphism. Therefore, we present the results for the Gln27Glu polymorphism and show potential mediating/modulating role of the Arg16Gly polymorphism by evaluating the effect of six common compound genotypes of these two polymorphisms.

CVDs and cancers were selected as the most common aging-associated diseases studied on their associations with common variants of the ADRB2 gene. An overall longevity phenotype was defined as reaching a certain old age at the end of the follow-up period or at date of death. For the purpose of the study, cut-offs between long and short life were left flexible ranging from the youngest possible age to the oldest possible age.