Aging and CR effects on the Plasma Membrane Redox System

来自我们实验室和其他实验室的数据表明，质膜氧化还原系统至少在一定程度上负责在饮食和衰老诱导的氧化应激挑战中维持抗氧化能力。在CR期间发生的质膜氧化还原系统的上调降低了老化的膜的氧化应激水平。CR通过降低NADH水平来延长酵母的寿命，这将把这种干预与质膜NADH依赖的脱氢酶联系起来。铬可以改变质膜中脂肪酸的组成，从而减少氧化损伤，包括脂质过氧化。更重要的是，随着年龄的增长，质膜氧化还原活性和辅酶Q含量增加，而CR对磷脂起到保护作用，阻止了脂质过氧化反应的进行。 我们正致力于培育转基因动物，并敲除与抗氧化剂系统有关的不同脱氢酶。我们成功地构建了NQO1和Cyt-b5-还原酶过表达基因，获得了NQO1和NRF2 KO动物。我们正在进行长寿研究和短期干预，以全面描述这些新的小鼠品系。 在与Placido Navas博士的实验室合作中，我们已经证明了Cyt-b5-还原酶的酿酒酵母同源物NQR1驻留在质膜上，当过度表达时，延长了复制和时间上的寿命。我们证明了NQR1通过将细胞转移到呼吸代谢和减少吡啶核苷酸池而不改变NAD/NADH比率，以Sir2依赖的方式延长了复制寿命。相反，按时间顺序延长寿命是通过与Sir2无关的乙醇产量下降来实现的。我们得出结论，NQR1通过其对酵母代谢的影响，是CR延长寿命的关键介质，并讨论了这些发现如何暗示该蛋白在哺乳动物寿命延长中的功能。

Data from our laboratory and others, have demonstrated that the plasma membrane redox system is, at least in part, responsible of the maintenance of the antioxidant capacity during oxidative stress challenges induced by the diet and aging. The upregulation of the plasma membrane redox system that occurs during CR decreases the levels of oxidative stress in aged membranes. CR extends life span of yeasts by decreasing NADH levels, which would connect this intervention to plasma membrane NADH-dependent dehydrogenases. CR modifies composition of fatty acid in the plasma membrane, resulting in decreased oxidative damage including lipid peroxidation. More importantly, plasma membrane redox activities and also the content of CoQ, which decline with age, are enhanced by CR providing protection to phospholipids and preventing the lipid peroxidation reaction progression. We are focusing our efforts on the generation of transgenic and knock out animals of the different dehydrogenases involved in this antioxidant system. We have successfully created NQO1 and Cyt-b5-reductase overexpressors and obtained NQO1 and NRF2 KO animals. We are setting longevity studies as well as short term interventions to fully characterize these new mouse lines. In collaboration with the laboratory of Dr. Placido Navas we have shown that the Saccharomyces cerevisiae homolog of Cyt-b5-reductase, NQR1, resides at the plasma membrane and when overexpressed extends both replicative and chronological lifespan. We demonstrated that NQR1 extends replicative lifespan in a SIR2-dependent manner by shifting cells towards respiratory metabolism and decreasing the pyridine nucleotide pool without altering the NAD+/NADH ratio. Chronological lifespan extension, in contrast, occurs via a SIR2-independent decrease in ethanol production. We conclude that NQR1 is a key mediator of lifespan extension by CR through its effects on yeast metabolism and discuss how these findings could suggest a function for this protein in lifespan extension in mammals.