that NOS variability can influence age-associated traits and survival also in the Northern European population.

female population (p = 0.024), adding the evidence that the gene can have a role in the quality of aging too, at least in the Danish population.

A major effect on ADL score was also observed for the UQCRFS1 gene in the male sample, which unfavorable association with ADL in the sub- sample converges in a correlation with a lower survival chance in the whole sample studied. This protein, Ubiquinol-Cytochrome C Reduc- tase, Rieske iron–sulfur polypeptide 1, is a subunit of Complex III of themitochondrialrespiratorychain.Its variabilityhasneverbeeninves- tigated in relation to human longevity and related phenotypes; howev- er, considering that the proper functioning of mitochondrial respiration is crucial for the cellular homeostasis and its de-regulation can increase oxidative stress, the observed result suggests the importance of an effi- cient oxidative phosphorylation for maintaining a good level of activity and independence in daily occupations after the ninth decade of life.

Possiblelimitationsofthepresentstudycanbefoundinthemethod- ology of the gene-based approach itself, which allows to identifying an effect on specific phenotypes but lacks in establishing the direction of this effect. For such a reason, favorable or unfavorable effects can be de- duced at single SNP level only. Furthermore, the male sample is may be undersized respect to the female one: this unbalance in sample compo- sition, although common in association studies with longevity, due to the sex-ratio characterizing long-lived cohorts (Passarino et al., 2002), can explain the inconsistent findings between the two genders, when separately considered.

5. Conclusions

In the whole sample as in the two genders separately, a broadly pro- tective role for the maintenance of a good functional status seems to be deserved totheglutathione(GSH)sub-pathway.Inparticular,genesbe- longing to the GSH sub-pathway were associated with WS (GCLC) and MMSE levels (GLRX and GSTP1) in the whole sample. In males, GPX4 and GCLC variability were found associated with ADL and HG strength, respectively. In females, the association between GLRX and HG hold also for the multiple comparison correction (p = 0.001), further sug- gesting that GSH metabolism can have an effect on functional status at old age. Such an effect may be linked to oxidative stress response, but also to other cellular mechanisms controlled by this metabolic way. The genes found associated with functional status in this work belong to the Free -Radical Induced Apoptosis pathway (http://www.biocarta.com/ pathfiles/h_freePathway.asp) activated in endothelial cells as a response to inflammation-related oxidative stress and playing a role insusceptibil- ityto cancer, and otherdiseases. As anexample,polymorphisms ofGSTP1 were found associated with different cancers and chemotherapy re- sponse (Sekine et al., 2007; Strange and Fryer, 1999), while mutations at GCLC locus have been associated with myocardial infarction (Koide et al., 2003). Furthermore, the apoptotic events activated by GSH sub- pathway in endothelial cells for resisting to oxidativestress have beenin- volved in the development and progression of atherosclerosis (Ballatori et al., 2009), another clinical conditions typical of old age. On the whole, this is the first work demonstrating an influence of GSH sub-pathway in age-related non pathological phenotypes, which may influence the qual- ity of aging.

In conclusion, this work supports a role of the pro–anti-oxidant pathway in physical and cognitive status after the ninth decade of life, particularly evidencing the effect of some sub-pathways, as UCP, Gluta- thione and thioredoxin pathways for the maintenance of functional sta- tusat old age. Therole of thesegenes in the preservationof physical and cognitive statusmaybeinfluenced bygender,suggestingpossible inter- actionswithendocrinesystems, inlinewith recentevidences indicating a role of oxidative stress in the aging of the endocrine system, converg- ing on the induction or regulation of inflammatory status typical of old age (Vitale et al., 2013). In addition, a new association was reported in relation to MMSE levels, related to metallothionein gene MT1A, which open new ways of investigations of this gene family in relation to cogni- tive functioning in humans.

It is clear that final conclusions on the role of the genetic variants on stress mechanisms can be drawn only after confirmation by functional analyses. However, we believe that all the associations found in this study deserve attention for future replications studies.

In general, the variability of genes affecting stress response in differ- ent individuals and populations deserve future studies. In fact, although oxidativestresspathwayhas been extensively characterized from a bio- chemical and molecular point of view, thanks to experimental models and knock out approaches, population association studies investigating the role of genetic variability in genes coding for proteins belonging to the oxidative stress cascade, as key point regulators such as NFkB or MAP kinases, are still scarce. Instead, a deeper knowledge of the genetic background able to provide a more or less efficient stress response and influence age-associated traits can help to understand the link between stress response and human aging, finally adding a piece to the complex scenario of determinants of human longevity.