Chronic and inflammatory diseases steadily stimulate conditions of stress that accelerate the aging process of tissues. Such an aberrant series of events impairs the molecular and functional regulation of the stress response of cells leading to an increased allostatic load and to the other hand to a poor responsiveness to stressors and metabolic compliance of tissues, which ultimately combine to develop the frailty phenotype of premature (unhealthy) aging. Pathogenic consequences of these events include defects in the mechanisms of repair and regeneration of tissues (stem cell function), host defence and the immune surveillance of tumours, response to hormones (such as insulin) and other metabolic signals. These events referred as to the “allostatic load hypothesis” of accelerated aging stimulated a series of studies aimed at deciphering the molecular mechanisms that link together the defect of the stress response with the exposure to conditions of chronic stress generated by the onset of age-related disorders. Once identified these mechanisms are expected to shield light on novel and more effective anti-aging strategies. Recent work in our group [1] has demonstrated that the response to stressogenic events, such as the exposure to Selenium-containing drugs or to reactive species such as hydrogen peroxide, include the up-regulation of genes (some in the family of glutathione S-transferases) that promote at the same time a detoxification response against the cellular stressors and a negative feedback on the transcriptional machinery (that dependent on Nrf2 transcription factor) activated during the stress response. That feedback appears to depend on a protein-protein interaction mechanism described for the first time in these laboratories [2]. This appears to represent a coordinated physiological mechanism of control for the stress response aimed at limit the metabolic and signaling impact of the response keeping it compatible with the homeostatic compensation and repair of damages, avoiding activation of cell death programs or degeneration of tissues by hyper-catabolism and necrotic death. Under circumstances of chronic stress, this mechanism of control may lose its physiological role thus assuming the characteristics of a causal event for the aforementioned defect of stress response observed in premature aging. Accordingly, we and others (reviewed in [3]) described an overexpression of GSTP protein and a defective transcription of Nrf2 in blood cells of chronic kidney disease (CKD) patients, a well-known model of allostatic load and premature aging (reviewed in [4, 5]). A defective Nrf2 expression has also been observed in skeletal muscle biopsies of these patients (Garibotto et al., personal communication). Another example of how the exposure to conditions of chronic stress can impair the stress response of tissues and cause premature aging is that of non-alcoholic fatty liver disease (NAFLD). In vitro and in vivo models of NAFLD clearly develop mechanisms of lipotoxicity and then of chronic stress that promote allostatic load and concomitantly repress genes responsible for the lipid metabolism and detoxification of the liver [6-8]. Tumorigenesis and metabolic sufferance of this organ and then of other systems, such as the adipose and muscle tissue, are main clinical consequences of such lipid disorder. Among the repressed genes, some members in the superfamily of cytochrome P450 with a key role in the metabolism of long-chain fatty acids, inflammatory lipids, vitamin E and omega-3 fatty acids [8, 9] are included. The repression of nuclear receptors responsible for the transcriptional control of these genes has been demonstrated in close mechanistic analogy with the Nrf2 repression process described above in CKD patients. Recently a defective Nrf2 activity was preliminarily identified in choline-deficiency model of murine fatty liver (Bartolini et al. unpublished data). The role of GSTP overexpression in the concomitant control of Nrf2 and nuclear receptors such as PPAR-g and SREBP-2, is under investigation. These pieces of emerging evidence support the need for further mechanistic studies on the stress response of normal and pathologic aging. The existence of molecular players, such as the GSTP gene, that may promote regulatory interactions at the interface between detoxification processes and the stress response, paves the way to targeted anti-aging strategies deserving clinical investigation.