Mitochondrial production of reactive oxygen species and incidence of age-associated lymphoma in OF1 mice: effect of alternate-day fasting.

There is currently of a great interest investigating the role of nutrition in the prevention of age-associated disorders. The present study aimed to evaluate, on a particular strain of mice, the efficacy of alternate-day fasting on the mitochondrial production of free radical species and on the incidence of a specific cancer (lymphoma) in aged mice. Alternate fasting, that was initiated in middle age mice through a 4 month period, reduced significantly the incidence of lymphoma (0% versus 33% for controls). No remarkable difference was observed in the overall food consumption between alternate-fed (AF) and ad libitum (AL) mice, suggesting that the efficacy of alternate fasting did not really depend on calorie restriction. A significant decrease in the mitochondrial generation of reactive oxygen species (ROS) that was associated with a significant increase in spleen mitochondria SOD activity was observed when mice were maintained on intermittent fasting. Our results suggest that alternate fasting could exert a beneficial antioxidant effect and a modulation of the oxidative stress associated with aging.

The effect of a water-dispersible beta-carotene formulation on the prevention of age-related lymphoid neoplasms in mice.

There is currently a great interest in the efficiency of micronutrients against age-associated disorders. The present study aimed to evaluate the efficacy of beta-carotene on the incidence of lymphoid neoplasia, a fatal pathology associated with OFI mouse ageing. Beta-carotene, given as a water-dispersible preparation to 8-month-old mice, on a four month follow-up study, significantly reduced the incidence of neoplasm (12.5% versus 50% for controls). Evaluation of the parameters of oxidative stress showed a highly-significant reduction of the antioxidant defenses in the liver of cancer mice when compared to healthy controls (78% decrease in GSH-Px activity and 47% decrease of the ratio GSH/GSSG). Liver GSH-Px activity was 35% higher in old than in young mice, which correlated with higher (41%) plasma Se level. In conclusion beta-carotene improved the antioxidant status of the mice, causing a 4.5-fold increase in the liver GSH/GSSG ratio, an effect which was probably responsible for the lowered incidence of neoplasia observed.

Iodine and/or selenium deficiency alters tissue distribution pattern of other trace elements in rats.

Tissue distribution of Fe, Mn, Cu, and Zn, the essential trace elements associated with oxidant and/or antioxidant processes, was examined in iodine- and/or selenium-deficient rats (ID, SeD, ISeD). Fe and Mn were the most affected minerals in all types of deficiency states. Mn levels decreased significantly in the liver in all deficiency states (approx 20-30%), in the heart in ID and SeD rats (approx 30-35%) and in the testis in ID rats (approx 15%). Whereas Mn enhancement was noted in kidney (approx 45%) and plasma in SeD and ISeD (approx 20% and 50%, respectively) animals. However, most striking alterations were seen with Fe. Significant elevation of Fe concentrations were observed in all deficiency states in the kidney (approx 90-125%) and heart (approx 20-25%), and in the liver in SeD (approx 35%) and ISeD (approx 75%) rats, whereas significant (approx 20%) Fe enhancement in the testis was observed only in ISeD animals. Lower Cu (approx 10-15%) and higher Zn (approx 10-20%) concentrations in heart tissues in all deficiency states were found; higher Zn (approx 20-35%) in the kidney of SeD and ISeD rats, and lower Cu in the testis of SeD animals were observed. In brain tissue, no alteration was seen in Fe, Mn, and Zn content, however, significantly increased (approx 15-20%) Cu concentrations were noted in all deficiency states. The results of this study indicated that iodine and/or selenium deficiency may modify the distribution and the homeostasis of other minerals.

Overexpression of cellular prion protein induces an antioxidant environment altering T cell development in the thymus.

Cellular prion protein (PrP(C)) is an ubiquitously expressed glycoprotein whose roles are still widely discussed, particularly in the field of immunology. Using TgA20- and Tg33-transgenic mice overexpressing PrP(C), we investigated the consequences of this overexpression on T cell development. In both models, overexpression of PrP(C) induces strong alterations at different steps of T cell maturation. On TgA20 mice, we observed that these alterations are cell autonomous and lead to a decrease of alphabeta T cells and a concomitant increase of gammadelta T cell numbers. PrP(C) has been shown to bind and chelate copper and, interestingly, under a copper supplementation diet, TgA20 mice presented a partial restoration of the alphabeta T cell development, suggesting that PrP(C) overexpression, by chelating copper, generates an antioxidant context differentially impacting on alphabeta and gammadelta T cell lineage.

Expression of prion protein increases cellular copper binding and antioxidant enzyme activities but not copper delivery.

The N-terminal region of the prion protein PrP(C) contains a series of octapeptide repeats. This region has been implicated in the binding of divalent metal ions, particularly copper. PrP(C) has been suggested to be involved in copper transport and metabolism and in cell defense mechanisms against oxidative insult, possibly through the regulation of the intracellular CuZn superoxide dismutase activity (CuZn-SOD) or a SOD-like activity of PrP(C) itself. However, up to now the link between PrP(C) expression and copper metabolism or SOD activity has still to be formally established; particularly because conflicting results have been obtained in vivo. In this study, we report a link between PrP(C), copper binding, and resistance to oxidative stress. Radioactive copper ((64)Cu) was used at a physiological concentration to demonstrate that binding of copper to the outer plasma cell membrane is related to the level of PrP(C) expression in a cell line expressing a doxycycline-inducible murine PrP(C) gene. Cellular PIPLC pretreatment indicated that PrP(C) was not involved in copper delivery at physiological concentrations. We also demonstrated that murine PrP(C) expression increases several antioxidant enzyme activities and glutathione levels. Prion protein may be a stress sensor sensitive to copper and able to initiate, following copper binding, a signal transduction process acting on the antioxidant systems to improve cell defenses.

Prion infection impairs copper binding of cultured cells.

The molecular mechanism of neurodegeneration in transmissible spongiform encephalopathies (TSEs) remains unclear. Using radioactive copper ((64)Cu) at physiological concentration, we showed that prion infected cells display a marked reduction in copper binding. The level of full-length prion protein known to bind the metal ion was not modified in infected cells, but a fraction of this protein was not releasable from the membrane by phosphatidylinositol-specific phospholipase C. Our results suggest that prion infection modulates copper content at a cellular level and that modification of copper homeostasis plays a determinant role in the neuropathology of TSE.