Contents lists available at ScienceDirect Mechanisms of Ageing and Development journal homepage: www.elsevier.com/locate/mechagedev    

Mechanisms of Ageing and Development

journal homepage: www.elsevier.com/locate/mechagedev

receptor gene polymorphisms as systemic determinants of aging in an evolutionary context

M. Kulminski a,b,*, Irina Culminskaya a,b, Svetlana V. Ukraintseva a,b, Konstantin G. Arbeev a,b, C. Land a,b, Anatoli I. Yashin a,b

aCenter for Population Health and Aging, Duke University Population Research Institute, USA bDepartment of Sociology, Duke University, USA

A B S T R A C T

The Gln27Glu polymorphism but not the Arg16Gly polymorphism of the beta2-adrenergic receptor (ADRB2) gene appears to be associated with a broad range of aging-associated phenotypes, including 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 risks of cancer, MI and IC, whereas the Glu27 allele or, equivalently, the Gly16Glu27 haplotype tends to be protective against these diseases. Genetic associations with longevity are of opposite nature at young- old and oldest-old ages highlighting the phenomenon of antagonistic pleiotropy. The mechanism of antagonisticpleiotropyisassociatedwithanevolutionary-drivenadvantageofcarriersofaderivedGln27 allele atyoungeragesandtheir survivaldisadvantageatolderagesasaresultofincreasedrisksofcancer, MI and IC. The ADRB2 gene can play an important systemic role in healthy aging in evolutionary context that warrants exploration in other populations.

 2010 Elsevier Ireland Ltd. All rights reserved.

of their involvement not only in vascular responses but also in pulmonary, endocrine, and central nervous systems functioning (Brodde, 2008a,b). Specifically, the roles of Arg16Gly and Gln27Glu polymorphisms in the pathophysiology of diseases of the heart (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 disease (Yu et al., 2008), COPD (Matheson et al., 2006), and cancer (Huang et al., 2001) have been studied in different populations.

1. Introduction

The etiology of complex phenotypes entails epistatic and gene- environment interactions that makes 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 receptors family that mediates the physiological effects of the hormone epinephrine and the neurotransmitter norepinephrine. Adrenergic stimulation of the ADRB2 influences, for instance, 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 ofamino 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 of a broad nature because

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 pathway(s) which 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

* Corresponding author at: Center for Population Health and Aging, University, Trent Hall, Room 002, Box 90408, Durham, NC 27708, USA. Tel.: +1 919 684 4962; fax: +1 919 684 3861. E-mail address: Alexander.Kulminski@duke.edu (A.M. Kulminski).

0047-6374/$ – see front matter © 2 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mad.2010.04.001

Table 1

Meanage(MA)andstandarddeviation(SD)forcarriersofeachgenotypeoftheADRB2Gln27GluorArg16GlypolymorphismatfirstFHSOexamination,andnumberofmenand women carrying given compound genotypes of the Gln27Glu and Arg16Gly polymorphisms in the sample of the genotyped FHSO participants.

Men Women MA (years) SD (years) Gln27Gln Gln27Glu Glu27Glu MA (years) SD (years) Gln27Gln Gln27Glu Glu27Glu MA (years) 37.2 36.4 35.0 35.5 36.3 36.4 SD (years) 9.3 10.2 9.5 8.9 9.7 10.1 Arg16Arg 36.9 8.9 103 0 0 36.5 8.7 101 2 0 Arg16Gly 36.8 10.1 113 235 2 35.3 9.4 125 236 0 Gly16Gly 35.7 9.8 33 151 144 36.6 9.9 32 140 148

systemic effect. The released data have information on the Arg16Gly and the Gln27Glu polymorphisms for 1565 (784 women) subjects. All genotyped members (but one) of the FHSO cohort participated in the 1st (1971–1974) and the 6th (1996–1997) examinations. There were 147 deaths (93 deaths occurred among men) in this sample that occurred after the 6th examination.