) Nitric oxide synthases: reg- ulation and function. Eur Heart J

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Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G,

biogenesis and function. In fact, nos3-/- mice have fewer mitochondria, and lower b-oxidative activity and energy expenditure than wild-type controls (Nisoli et al. 2003; Le Gouill et al. 2007). In this context, it is also worth noting that recent studies have reported the existence of a mitochondrial NOS (mtNOS) isoform that seems to be both constitutive, mainly a post- translational isoform of NOS1, and inducible (Elfering et al. 2000; Lo`pez et al. 2006; Finocchietto et al. 2009). Because of its action on complex I and IV, NO in mitochondria may have important effects on oxidative phosphorylation and ROS/RNS production (Finocchietto et al. 2009). These effects may be amplified in a pro-oxidant environment like in the case of aged individuals, with consequences particularly in tissues such as brain and skeletal muscle which are highly dependent on mitochondrial function.

causative genetic variations in LD with the studied SNPs remain to be identified and that the associations between NOS alleles and aging phenotypes we observed, in most cases would not hold after Bonfer- roni correction for multiple comparisons, indicating that it will be useful to replicate this study. On the other hand, this study availed of a population (Calabria, Southern Italy) which is characterized by high genetic homogeneity and a scarce level of immigration due to geographical, historical and social reasons. Conse- quently it is likely we avoided false positive results due to population stratification. On the other hand, it is also important to underline that all the results were in line with previous data and in particular with data from model organisms. This allows us to consider NOS genes to have an important role on the age related homeostatic and physiological decline which is at the basis of most of the age related phenotypes and longevity (Fried et al. 2001; Montesanto et al. 2010).

Acknowledgments The research leading to these results has received fundingfromthe EuropeanUnion’sSeventh Framework Programme (FP7/2007-2011) under Grant agreement No. 259679 and from ‘‘Fondi di Ateneo’’ of the University of Calabria.

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