We found that two SNPs, rs282070 on intron 1 of MAP3K7 gene and rs2111699 on intron 1 of GSTZ1 gene, were significantly associated with survival at advanced age after Bonferroni's correction. GSTZ1 is also implicated in the cellular response to environmental insults. GSTZ1 is a member of the glutathione S-transferase (GSTs) superfamily of multifunctional enzymes which are involved in cellular detoxification, via conjugation with glutathione (GSH), of a wide range of endogenous and exogenous toxic compounds, and various reactive products generated under oxidative stress. Diverse cellular functions, ranging from apoptosis to cell survival, are also modulated by GSTs (Nebert and Vasiliou 2004; Hayes et al. 2005; Laborde 2010).

The GSTs comprise three families of genes designed as cytosolic, mitochondrial, and microsomal transferase. The cytosolic GSTZ class of GSTs is expressed in many eukaryotic species, including fungi, plants, insects, and mammals (Board et al. 1997). Human GSTZ1, which is identical to maleylacetoacetate isomerase, catalyzes two distinct reactions: the biotransformation of a range of-haloacids, including dichloroacetic acid, a drinking water contaminant, and the GSH-dependent isomerization of maleylacetoacetate to fumarylacetoacetate, the penultimate step in the phenylalanine tyrosine.

MAP3K7 (also known as transforming growth factor-activated kinase-1) is a serine/threonine kinase, a member of the mitogen-activated protein kinase kinase kinase family, which plays a crucial role in interleukin 1, tumor necrosis factor, and Toll-like receptor signaling pathways. Various stressors and inflammatory cytokines trigger the activation of MAP3K7 which in turn activates key intracellular kinases such as the p38 MAPK, c-jun N-terminal kinase, and I-kappa B kinase complex. These pathways ultimately activate transcription factors nuclear factor-kappa B and activator protein-1 which are critical regulators of genes of the immune-inflammatory responses (Ninomiya-Tsuji et al. 1999; Sato et al. 2005; Chen et al. 2006; Landstrm 2010).

Studies have also demonstrated that the oxidative stress caused by reactive oxygen species (ROS) may induce or mediate the activation of the MAPK pathways, including the one mediated by MAP3K (Son et al. 2011 for a review). In particular, Omori et al. (2008) reported that MAP3K7 regulates the levels of ROS and prevents inflammation. Thus, MAP3K7 may be allelic variants differently affecting the transcriptional rate, but linkage disequilibrium of these SNPs with other functional variants is also possible. This is an interesting issue that needs to be investigated in future research.

Nevertheless, we believe that our results reinforce the view (synthesized in the oxidation inflammatory theory of aging, see De la Fuente and Miquel 2009) that the immune, inflammatory, and stress responses, which are essential components of the body's network of defense against external and internal damaging agents, play an essential role in life span and in age-related phenotypes.

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