Polymorphisms in the superoxidase dismutase reveal no association with human longevity in Germans: a case–control association study

Liljana Gentschew • Friederike Flachsbart • Rabea Kleindorp • Nandini Badarinarayan • Stefan Schreiber • Almut Nebel

Received: 31 May 2013/Accepted: 20 September 2013/Published online: 22 October 2013  Springer Science+Business Media Dordrecht 2013

SNPs in our extensive collection of 1,612 long-lived individuals (centenarians and nonagenarians) and 1,104 younger controls. Furthermore, we intended to replicate the previous association of the SOD2 SNP rs4880 with longevity observed in a Danish cohort. In our study, no association was detected between the tested SNPs and the longevity phenotype, neither in the entire long-lived sample set nor in the centenarian subgroup analysis. Our results suggest that there is no considerable influence of sequence variation in the SOD genes on human longevity in Germans.

in aging and oxidative stress regulation has been widely studied and there is growing evidence that imbalances in these processes influence lifespan in several species. In humans, genetic polymorphisms in SOD genes may play an important role in the development of age-related diseases and genetic variation in SOD2 is thought to be associated with longevity. These observations prompted us to perform a case–control association study using a comprehen- sive haplotype tagging approach for the three SOD genes (SOD1, SOD2, SOD3) by testing a total of 19

Liljana Gentschew and Friederike Flachsbart have contributed equally to this study.

Introduction

Electronic supplementary material The online version of this article (doi:10.1007/s10522-013-9470-3) contains supple- mentary material, which is available to authorized users.

of multiple genetic and environmental factors. Based on epidemiological studies, approximately 30 % of inter-individual variation in adult lifespan is attributed to genetic parameters whereas environmental factors account for the remaining 70 % (Herskind et al. 1996; Hjelmborg et al. 2006; Ljungquist et al. 1998; Skytthe et al. 2003). Interestingly, most long-lived individuals (LLI) stay healthy with a delayed onset of age-related diseases such as coronary heart disease, neurodegen- erative disease and cancer (Schoenhofen et al. 2006; Sebastiani and Perls 2012). It has been proposed that their genetic composition differs from that of average-

L. Gentschew   F. Flachsbart   R. Kleindorp  N. Badarinarayan   S. Schreiber   A. Nebel (&) Institute of Clinical Molecular Biology, Christian- Albrechts-University of Kiel, Schittenhelmstraße

,

Kiel, Germany e-mail: a.nebel@mucosa.de

S. Schreiber

Clinic for Internal Medicine I, University Schleswig-Holstein, Kiel, Germany

Popgen Biobank, Christian-Albrechts-University, Kiel, Germany

lived individuals in the following aspects: (i) LLI carry a reduced number of risk alleles for age-related diseases and/or (ii) LLI are particularly enriched for beneficial variants in so-called ‘‘longevity-assurance genes’’ (Newman et al. 2010; Perls et al. 2002).

expression of SOD2 in adult Drosophila melanogaster resulted in an increased lifespan that is proportional to the increased expression of the enzyme (Sun et al. 2002). Similar effects were observed in mice over- expressing SOD2 or SOD1 (Hu et al. 2007; Orr and Sohal 1994), whereas mice with conditional SOD2 deficiency in fibroblasts showed a reduced lifespan and premature onset of age-related phenotypes such as weight loss, skin atrophy, osteoporosis and muscle degeneration (Treiber et al. 2011). Mice deficient in SOD3 also displayed a shorter life (Elchuri et al. 2005).

suggest that the accumulation of reactive oxygen species (ROS) cause the alteration of physical or cognitive functions with aging (Harman 1956). To date, most of the research in the area of longevity supports this hypothesis (reviewed in Bokov et al. 2004). However, some studies have shown that a moderate level of oxidative stress might have positive effects on lifespan as put forward by the hormesis hypothesis (Rattan 2010; Rattan and Demirovic 2009; Ristow and Zarse 2010). High levels of ROS are responsible for the onset of various common diseases that are associated with a decreased lifespan including hypertension (Lassegue and Griendling 2004), athero- sclerosis (Kaneto et al. 2010; Morrell 2008), type 2 diabetes (Kaneto et al. 2010), cancer (Waris and Ahsan 2006) and Alzheimer’s disease (Benzi and Moretti 1995). It is possible that LLI carry beneficial genetic variants in longevity-assurance genes that are involved in stress response signaling or help to protect against oxidative damage caused by free radicals

2005).