ledom jdA

pledoMperocs-zpledoMperocs-zpledoMperocs-zpledoMperocs-z jdAledoMjdAledoMjdAledoMjdAledoM ledom jdA

For two of the six variants analyzed we found association with geriatric conditions but not with longevity. Specifically the SNP rs2682826 in the NOS1 gene and the SNP rs10277237 in the NOS3 gene were respectively associated with GDS (p = 0.015; p = 0.033) and Activity of Daily Model Adj Living (p = 0.002; p = 0.004), two of the main Model Adj factors affecting quality of life in older individuals. Depression is a complex disorder where, inflammation, oxidative/nitrosative stress, and reduced hippocampal neurogenesis make a substantial contribution (Maes et al. 2009). It has been found that NOS1-derived NO negatively affects neurogenesis and that the over- expression of NOS1 in the hippocampus following chronic mild stress exposure suppresses hippocampal neurogenesis and induces depression (Zhou et al. 2007). We found that carriers of the minor rs2682826-T allele have a higher probability to be depressed. In line with our observation, the rs2682826-T allele has been found to be a susceptibility factor for recurrent depressive disorder, and for traits where depression is a co- morbidity factor such as Parkinson disease (Gałecki et al. 2011; Hancock et al. 2008). The rs2682826 is located in the 30UTR of exon 29, downstream from the translation termination site of the NOS1 (C276T). Differences in protein production elicited by this variation, that lies close to several miRNAs binding sites (Ibarrola-Villava et al. 2011) could be at the basis of the observed association.

Another interesting finding of our study was the association between the NOS3 rs10277237 and ADL scores. Subjects homozygous for the rs10277237-A allele had significantly better ADL performance compared with subjects with the other two genotypes. The inability of older adults to perform basic self care independently is a consequence of a decline in physiological functions of multiple tissues. A contrib- utor to this general decay is likely to be the reduction in endothelial cell function caused by the age-related impairment in the release of NO by NOS3. Indeed, this has the effect of reducing blood flow to all tissues in the body and thus the availability of nutrients for energy needs. Age-related changes in energy pro- duction and fuel utilization via mitochondrial dys- function may also contribute to the decline in physical performance and disability among older adults. To this regard, evidence in literature indicate that NO

Beckman JS, Koppenol WH (

) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol

:C

–C

Bros M, Boissel JP, Go¨dtel-Armbrust U, Fo¨rstermann U (

) Transcription of human neuronal nitric oxide synthase

NAs derived from different first exons is partly con- trolled by exon

-specific promoter sequences. Genomics

:

–

Brown GC (

) Nitric oxide and neuronal death. Nitric Oxide

:

–

Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AM (

) Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci

:

–

Calcerrada P, Peluffo G, Radi R (

) Nitric oxide-derived oxidants with a focus on peroxynitrite: molecular targets, cellular responses and therapeutic implications. Curr Pharm Des

:

–

Calle ML, Urrea V, Malats N, Van Steen K (

) mbmdr: an R package for exploring gene–gene interactions associated with binary or quantitative traits. Bioinformatics

:

–

Cau SB, Carneiro FS, Tostes RC (

) Differential modulation of nitric oxide synthases in aging: therapeutic opportuni- ties. Front Physiol

:

Colas D, Gharib A, Bezin L, Morales A, Guidon G, Cespuglio R, Sarda N (

) Regional age-related changes in neuronal nitric oxide synthase (

OS), messenger RNA levels and activity in SAMP

brain. BMC Neurosci

:

De Rango F, Montesanto A, Berardelli M, Mazzei B, Mari V, Lattanzio F, Corsonello A, Passarino G (

) To grow old in southern Italy: a comprehensive description of the old and oldest old in Calabria. Gerontology

:

–

Dere E, De Souza Silva MA, Topic B, Fiorillo C, Li JS, Sadile AG, Frisch C, Huston JP (

) Aged endothelial nitric oxide synthase knockout mice exhibit higher mortality concomitant with impaired open-field habituation and alterations in forebrain neurotransmitter levels. Genes Brain Behav

:

–

Domek-Łopacin´ska KU, Strosznajder JB (

) Cyclic GMP and nitric oxide synthase in aging and Alzheimer’s disease. Mol Neurobiol

:

–

Drew B, Leeuwenburgh C (

) Aging and the role of reactive nitrogen species. Ann NY Acad Sci

:

–

Elfering SL, Sarkela TM, Giulivi C (

) Biochemistry of mitochondrial nitric-oxide synthase. J Biol Chem

:

–

Feil R, Kleppisch T (

) NO/

MP-dependent modulation of synaptic transmission. Handb Exp Pharmacol

:

–

Finocchietto PV, Franco MC, Holod S, Gonzalez AS, Converso DP, Arciuch VG, Serra MP, Poderoso JJ, Carreras MC (

) Mitochondrial nitric oxide synthase: a masterpiece of metabolic adaptation, cell growth, transformation, and death. Exp Biol Med (Maywood)

:

–

Folstein MF, Folstein SE, M

ugh PR (

) ‘‘Mini-mental state’’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res

:

–

Fo¨rstermann U, Sessa WC (

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

:

–

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