Increased protein synthesis is proposed as a mechanism of life-span extension during caloric restriction (CR). We hypothesized that CR does not increase protein synthesis in all tissues and protein fractions and that any increased protein synthesis with CR would be due to an increased anabolic effect of feeding. We used short- (4 hours) and long-term (6 weeks) methods to measure in vivo protein synthesis in lifelong ad libitum (AL) and CR mice. We did not detect an acute effect of feeding on protein synthesis while liver mitochondrial protein synthesis was lower in CR mice versus AL mice. Mammalian target of rapamycin (mTOR) signaling was repressed in liver and heart from CR mice indicative of energetic stress and suppression of growth. Our main findings were that CR did not increase rates of mixed protein synthesis over the long term or in response to acute feeding, and protein synthesis was maintained despite decreased mTOR signaling.

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Activation of NF-E2-related factor 2 (Nrf2) is a potential therapeutic intervention against endothelial cell oxidative stress and associated vascular disease. We hypothesized that treatment with the phytochemicals in the patented dietary supplement Protandim would induce Nrf2 nuclear localization and phase II antioxidant enzyme protein in human coronary artery endothelial cells (HCAECs), protecting against an oxidant challenge in an Nrf2- dependent manner. Protandim treatment induced Nrf2 nuclear localization, and HO-1 (778% of control ± 82.25 P < 0.01), SOD1 (125.9% of control ± 6.05 P < 0.01), NQO1 (126% of control ± 6.5 P < 0.01), and GR (119.5% of control ± 7.00 P < 0.05) protein expression in HCAEC. Treatment of HCAEC with H2O2 induced apoptosis in 34% of cells while pretreatment with Protandim resulted in only 6% apoptotic cells (P < 0.01). Nrf2 silencing significantly decreased the Protandim-induced increase in HO-1 protein (P < 0.01). Nrf2 silencing also significantly decreased the protection afforded by Protandim against H2O2- induced apoptosis (P < 0.01 compared to no RNA, and P < 0.05 compared to control RNA). These results show that Protandim induces Nrf2 nuclear localization and antioxidant enzyme expression, and protection of HCAEC from an oxidative challenge is Nrf2 dependent.

Oxidative stress is a component of many human diseases, including cardiovascular diseases (CVD). Exercise and various phytochemicals activate nuclear factor (erythroid-derived 2)-like 2 (Nrf2), the master regulator of antioxidant defenses, and attenuate CVD. This review highlights Nrf2 regulation by exercise and phytochemicals and the role of Nrf2 as a therapeutic target in CVD.

Lifespan is extended by rapamycin treatment, caloric restriction (CR), crowded litter (CL), and in genetic models such as the Snell Dwarf mouse. Various mechanisms have been proposed by which lifespan is extended in these rodent models, including improved antioxidant defenses. The transcription factor nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) has been suggested to be the “master regulator” of cellular antioxidant defenses. However, whether these rodent longevity models show enhanced Nrf2 activation and antioxidant enzyme expression is unknown. The purpose of this study was to determine the expression of Nrf2 and ARE‐regulated antioxidant enzymes in four rodent models of longevity. Endogenous antioxidant enzyme and Nrf2 expression were not consistently increased in long‐lived animals, with considerable variation existing between models. While Nrf2 and its targets were greater than controls in Snell liver and heart, antioxidant defenses were significantly lower than controls across all tissues in CL animals. CR resulted in increased antioxidant defenses in some, but not all, tissues. Rapamycin did not affect Nrf2‐regulated enzymes, but expression differed between sexes. Not all models of longevity displayed similar Nrf2‐regulated antioxidant enzymes and these data suggest that sex, age, and tissue specific differences must be considered with regard to antioxidant capacity and longevity.