and Anders 2011). Analysis of Gstz1-knockout mice provided more insight about the physiological role of Gstz1. Besides a range of pathological changes, Gstz1−/− mice display the induction of some of the cytosolic GST isoenzymes, and the constitutive ex- pression of genes that are regulated by antioxidant- response elements (AREs) and that respond to oxida- tive stress via the Keap1/Nrf2 signaling pathway, which regulates the expression of numerous detoxify- ing and antioxidant genes (Lim et al. 2004; Lee and Johnson 2004). All of these findings support the view that the lack of GSTZ1 may induce oxidative stress (Blackburn et al. 2006). The antioxidant role of GSTs is well known and derives essentially from their ability to regulate the concentration of GSH, the most pow- erful cellular antioxidant, in different cellular compart- ments including mitochondria, the principal source and target of ROS. For instance, specific mitochondri- al GST isoforms are able to protect mitochondria from oxidative insults either indirectly by maintaining ap- propriate levels of GSH or directly by reducing cellu- lar peroxides and reactive aldehydes, such as 4- hydroxynonenal, generated from lipid peroxidation (Raza 2011). The recent discovery that GSTZ1 also localizes in mitochondria (Li et al. 2011) leads to assume that GSTZ1 may also contribute to the cellular redox status and then may be relevant to aging and longevity. Interestingly, Starr et al. (2008) showed that the GSTZ1 R42G variant affects both telomere length, a biomarker of stress and physical aging, and suggest that this may occur through oxidative stress. Moreover it has been shown that the GSTZ1-1002 G>A variant influences cognitive ability in the elderly, probably because of its effect on dopamine production and dopamine by-product disposal (Starr et al. 2008). In our study, the rs2111699 resulted to be significantly associated to the longevity phenotype. It seems to act in a recessive manner, with the rs2111699-G allele favor- ing survival at very old age. To our knowledge, this is the first study reporting an association between GSTZ1 genetic variability and human survival. Overall, based on our data, it can be concluded that MAP3K7 and GSTZ1 are longevity genes whose var- ’ iability actually affects the organism s chances of

Acknowledgments The research leading to these results has received funding from the European Union’s Seventh Frame- work Programme (FP7/2007-2011) under grant agreement no. 259679 and from “Fondi di Ateneo” of the University of Calabria.

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