Effects of Longevinex (modified resveratrol) on cardioprotection and its mechanisms of action

Although resveratrol has been proven to possess diverse health benefits, several recent reports have demonstrated conflicting results on some aspects of its effects, including its anti-aging properties. Considerable debate appears to exist on the dose and bioavailability of resveratrol, leading to the controversies on its effectiveness. To resolve the problem, we designed a study with a resveratrol formulation that contained resveratrol supplemented with 5% quercetin and 5% rice bran phytate (commercially known as Longevinex). These ingredients were micronized to increase the bioavailability. Sprague-Dawley rats were gavaged with either Longevinex or vehicle (5% quercetin plus 5% rice bran phytate), and rats were sacrificed after 1 or 3 months, when isolated working hearts were subjected to 30 min ischemia followed by 2 h of reperfusion. Longevinex-treated hearts, irrespective of the duration of treatments, revealed superior cardiac performance, reduced infarct size, and induction of survival signals as evidenced by increased Bcl2/Bax ratio and enhanced Akt phosphorylation. In contrast, LC3-II and Beclin were enhanced significantly after 3 months of Longevinex treatment, suggesting that autophagy occurred only after feeding Longevinex to rats for a prolonged period of time. Corroborating with the results of autophagy, Sirt1 and Sirt3 increased significantly only after 3 months of Longevinex treatment, suggesting that enhanced expression of Sirts correlated with induction of autophagy. In concert, Longevinex caused phosphorylation and nuclear translocation of FoxO1, FoxO3a, and FoxO4, indicating involvement of FoxOs with autophagy. Since Sirts and FoxOs are reliable markers of longevity, the results appear to suggest that Longevinex induces longevity after prolonged feeding via induction of autophagy, while it converts death signals into survival signals and provides cardioprotection within a relatively shorter period of time.