Sanz Alberto, Caro Pilar, Ibañez Jorge, Gómez José, Gredilla Ricardo, Barja Gustavo
Department of Animal Physiology-II, Faculty of Biological Sciences, Complutense University, c/Antonio Novais-2, Madrid 28040, Spain.
J Bioenerg Biomembr. 2005 Apr;37(2):83-90. doi: 10.1007/s10863-005-4131-0.
Previous studies in mammalian models indicate that the rate of mitochondrial reactive oxygen species ROS production and the ensuing modification of mitochondrial DNA (mtDNA) link oxidative stress to aging rate. However, there is scarce information concerning this in relation to caloric restriction (CR) in the brain, an organ of maximum relevance for ageing. Furthermore, it has never been studied if CR started late in life can improve those oxidative stress-related parameters. In this investigation, rats were subjected during 1 year to 40% CR starting at 24 months of age. This protocol of CR significantly decreased the rate of mitochondrial H(2)O(2) production (by 24%) and oxidative damage to mtDNA (by 23%) in the brain below the level of both old and young ad libitum-fed animals. In agreement with the progressive character of aging, the rate of H(2)O(2) production of brain mitochondria stayed constant with age. Oxidative damage to nuclear DNA increased with age and this increase was fully reversed by CR to the level of the young controls. The decrease in ROS production induced by CR was localized at Complex I and occurred without changes in oxygen consumption. Instead, the efficiency of brain mitochondria to avoid electron leak to oxygen at Complex I was increased by CR. The mechanism involved in that increase in efficiency was related to the degree of electronic reduction of the Complex I generator. The results agree with the idea that CR decreases aging rate in part by lowering the rate of free radical generation of mitochondria in the brain.
以往在哺乳动物模型中的研究表明，线粒体活性氧（ROS）的产生速率以及随之而来的线粒体DNA（mtDNA）修饰将氧化应激与衰老速率联系起来。然而，关于大脑（与衰老高度相关的器官）中热量限制（CR）方面的相关信息却很少。此外，从未有人研究过在生命后期开始的热量限制是否能改善那些与氧化应激相关的参数。在本研究中，24月龄的大鼠在1年时间内接受40%的热量限制。这种热量限制方案显著降低了大脑中线粒体过氧化氢（H₂O₂）的产生速率（降低了24%）以及mtDNA的氧化损伤（降低了23%），使其低于老年和幼年自由进食动物的水平。与衰老的渐进性一致，大脑线粒体H₂O₂的产生速率随年龄保持恒定。核DNA的氧化损伤随年龄增加，而这种增加通过热量限制完全逆转至年轻对照组的水平。热量限制诱导的ROS产生减少定位于复合体I，且耗氧量没有变化。相反，热量限制提高了大脑线粒体在复合体I处避免电子泄漏到氧的效率。效率提高所涉及的机制与复合体I发生器的电子还原程度有关。这些结果支持这样一种观点，即热量限制部分通过降低大脑线粒体自由基的产生速率来降低衰老速率。
