Common polymorphisms in nitric oxide synthase (NOS) genes influence quality of aging and longevity in humans

Alberto Montesanto • Paolina Crocco • Federica Tallaro • Francesca Pisani Bruno Mazzei • Vincenzo Mari • Andrea Corsonello • Fabrizia Lattanzio • Giuseppe Passarino • Giuseppina Rose

Received: 29 January 2013/Accepted: 3 April 2013  Springer Science+Business Media Dordrecht 2013

NOS1 and NOS2 was associated with longevity. In addition NOS1 rs1879417 was also found to be associated with a lower cognitive performance, while NOS2 rs2297518 polymorphism showed to be associ- ated with physical performance. Moreover, SNPs in the NOS1 and NOS3 genes were respectively associ- ated with the presence of depression symptoms and disability, two of the main factors affecting quality of life in older individuals. On the whole, our study shows that genetic variability of NOS genes has an effect on common age related phenotypes and lon- gevity in humans as well as previously reported for model organisms.

Abstract Nitric oxide (NO) triggers multiple signal transduction pathways and contributes to the control of numerous cellular functions. Previous studies have shown in model organisms that the alteration of NO production has important effects on aging and life- span. We studied in a large sample (763 subjects, age range 19–107 years) the variability of the three human genes (NOS1, -2, -3) coding for the three isoforms of the NADPH-dependent enzymes named NO synthases (NOS) which are responsible of NO synthesis. We have then verified if the variability of these genes is associated with longevity, and with a number of geriatric parameters. We found that gene variation of

Keywords NOS  Longevity  Aging  Nitric oxide  Polymorphisms

Alberto Montesanto and Paolina Crocco contributed equally to this study.

Introduction

Electronic supplementary material The online version of this article (doi:10.1007/s10522-013-9421-z) contains supplementary material, which is available to authorized users.

supplementary material, which is available to authorized users.

Nitric oxide (NO) is one of the most widespread signaling molecules in nature. By interacting with different intracellular targets, NO triggers multiple signal transduction pathways thus contributing to the control of almost every cellular function (Liaudet et al. 2000). NO is produced during the oxidation of -arginine to -citrulline by a family of NADPH- L L dependent enzymes named NO synthases (NOS), with three isoforms in mammals encoded by three distinct NOS genes, named neuronal (nNOS or NOS1), induc- ible (iNOS or NOS2), and endothelial (eNOS or NOS3). Although all isoforms share a similar

A. Montesanto   P. Crocco coe F. Tallaro  F. Pisani   G. Passarino  G. Rose (&) Department of Biology, Ecology and Earth Science, University of Calabria,

Rende, Italy e-mail: pinarose@unical.it

Scientific Direction of Italian National Research Center on Aging (INRCA), 60124 Ancona, Italy

and that this is a key contributing factor to the onset of age related phenotypes such as vascular and brain aging (van der Loo et al. 2000; Taddei et al. 2001; Napoli and Ignarro 2009; Brown 2010; Kawamoto et al. 2012). Although the enhanced production of O - 2 that accompanies the aging process, as well as the age- related depletion of some essential NOS substrates and cofactors, may affect the amount of bioavailable NO, an impaired activity and expression of NOSs has been reported to occur with age which contributes to alterations in NO signaling, and to the subsequent failure of many of the body’s physiological processes (Yang et al. 2004; Strosznajder et al. 2004; Yoon et al. 2010; Cau et al. 2012; Jung et al. 2012).

are quite different. NOS1 and NOS3 are constitutively expressed and Ca2?/calmodulin-dependent, while the inducible form (NOS2) is induced by inflammatory stimuli and is Ca2?/calmodulin-independent (Fo¨rster- mann and Sessa 2012). The activity of each of these isoforms is fine-tuned by a variety of transcriptional and post-translational modifications, which may also influence the specific targeting of NOS to subcellular compartments (Oess et al. 2006). Although all three isoforms can be found in numerous tissues, the specific cell type where NOS enzymes are located is of critical importance in determining the specific outcomes of the NO signalling pathways (Villanueva and Giulivi 2010). In neuronal cells NO, which is produced principally by NOS1, functions as regulator of neuro- nal transmission, cerebral blood flow and synaptic plasticity thus acting as a neuromodulator and neuro- protective agent (Calabrese et al. 2007; Feil and Kleppisch 2008; Garthwaite 2008). In endothelial cells NO, mainly produced by NOS3, acts as a regulator of vascular homeostasis being involved in the regulation of smooth muscle relaxation, and in the inhibition of platelet aggregation (Kader et al. 2000; Moncada and Higgs 2006). NO produced by NOS2 particularly in macrophages, is mainly involved in the maintenance of the immune-inflammatory response (Moilanen et al. 1997; Wink et al. 2011). The biological effects of NO, however, largely depend on the amount of NO produced. High amounts of NO or its derivative reactive nitrogen species (RNS), such as peroxynitrite (ONOO–), a highly reactive radical produced by the reaction between NO and superoxide anion (O -), can trigger nitrosative modifications of 2 proteins, lipids and nucleic acids, which in turn may impinge on cellular signaling pathways leading to cytotoxicity, neurodegeneration, and apoptotic cell death (Beckman and Koppenol 1996; Pacher et al. 2007; Calcerrada et al. 2011). Oxidative stress is a well established hallmark of the