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Mechanisms of Ageing and Development

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

The Mn-superoxide dismutase single nucleotide polymorphism rs4880 and the glutathione peroxidase 1 single nucleotide polymorphism rs1050450 are associated with aging and longevity in the oldest old

Mette Soerensen a,b,*, Kaare Christensen a, Tinna Stevnsner c, Lene Christiansen a,b

aDanish Aging Research Center, Epidemiology, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense C, bDepartment of Biochemistry, Pharmacology and Genetics, Odense University Hospital, 5000 Odense C, Denmark cDanish Aging Research Center, Department of Molecular Biology, University of Aarhus, C.F. Moellers Alle´ 1130, 8000 Aarhus C, Denmark

A B S T R A C T

The free radical theory of aging states that reactive oxygen species (ROS) play a key role in age-related accumulationofcellulardamage,andconsequentlyinfluenceagingandlongevity.Therefore,variationin genesencoding proteins protecting against ROS could be expected to influence variation in aging and life span.Thers4880andrs1050450SNPsinthemanganesesuperoxidedismutase(MnSOD)andglutathione peroxidase 1 (GPX1) genes, respectively, are associated with age-related diseases and appear to affect the activities of the encoded variant proteins.

In this study we genotyped these SNPs in 1650 individuals from the Danish 1905 cohort (follow-up time: 1998–2008, age at intake: 92–93 years, number of deaths: 1589 (96.3%)) and investigated the association with aging and longevity. We found decreased mortality of individuals holding either the MnSOD rs4880 C or the GPX1 rs1050450 T alleles (HR (MnSOD(CC/CT)) = 0.91, P = 0, p = 0.002 and HR (GPX1(TT/TC)) = 0.93, p = 0.008). Furthermore, a synergetic effect of the alleles was observed (HR = 0.76, p = 0.001). Finally, moderate positive associations with good self rated health, decreased disability and increased cognitive capacity were observed. Our results thus indicate that genetic variation in MnSOD and GPX1 may be associated with aging and longevity.

  2009 Elsevier Ireland Ltd. All rights reserved.

tion adducts (e.g. 4-hydroxynonenal (HNE)) can be the results of ROS damage. HNE might subsequently give rise to the exocyclic etheno adducts of adenine, cytosine and guanine in DNA. More- over, exposure of nucleic acids to ROS can generate a wide variety of modified bases, 8-oxo-7,8-dihydroguanine (8-oxoguanine), which induces base-mispairing, being one of the most abundant. Furthermore, ROS exposure may also result in imidazol ring- opened derivatives of pyrimidines (FaPy products) and in single- strand breaks in DNA. Over time the sum of these alterations contribute to deleterious cellular changes leading to dysfunction of mitochondria, cells and ultimately of the organism, that is, the damage induced alterations contribute to aging and longevity (Harman, 1973; Harman, 1991). In addition, the damage induced alterations have been associated with certain cancers and cardiovascular and neurodegenerative disorders of old age (Antonella, 1999; Vijg, 2000).

1. Introduction

Genetic factors contribute to the variation in life span by approximately 25% (Herskind et al., 1996), a contribution believed to be minimal before age 60 years and most profound from age 85 years and onwards (Hjelmborg et al., 2006). The candidate genes encode proteins involved in several biological processes including the protection against oxidative stress (Christensen et al., 2006). Reactive oxygen species (ROS) are produced because approxi- mately 2–3% of the oxygen atoms taken up by the mitochondriaare reduced insufficiently (Valko et al., 2004). ROS can oxidize and damage nucleic acids, proteins and lipids hereby altering their stability and function. Thus, protein modifications (such as protein carbonylation and nitration) and the formation of lipid peroxida-

Among the antioxidant enzymes involved in protecting against ROS, the manganese superoxide dismutase (MnSOD) and the glutathione peroxidase 1 (GPX1) play primary roles via the dismutation of the superoxide anion (O  to hydrogen peroxide 2 (H O ) and the reduction of H O to H O, respectively. MnSOD is 2 2 2 2 2 localized in the mitochondria (Slot et al., 1986), while the GPX1

* Corresponding author at: Danish Aging Research Center, Epidemiology, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense C, Denmark. Tel.: +45 65412822.

Abbreviations: SNP, single nucleotide polymorphism; MnSOD, manganese hazard ratio; ADL, Activity of Daily Living; MMSE, Mini Mental State

0047-6374/$ – see front matter © 2 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mad.2009.01.005

longitudinal study of the long lived Danish 1905 cohort. Compared to a cross sectional set-up, a longitudinal set-up reduces the bias arising from cohort specific variations in environment. In addition, we investigated the associations of the SNPs with the functional and cognitive abilities of the elderly, since these phenotypes were previously shown to be important mortality risk factors in oldest old (Nybo et al., 2003).