Sastre J, Pallardó F V, Viña J
Departamento de Fisiología, Facultad de Medicina, Universitat de Valencia, Spain.
IUBMB Life. 2000 May;49(5):427-35. doi: 10.1080/152165400410281.
Harman first suggested in 1972 that mitochondria might be the biological clock in aging, noting that the rate of oxygen consumption should determine the rate of accumulation of mitochondrial damage produced by free radical reactions. Later in 1980 Miquel and coworkers proposed the mitochondrial theory of cell aging. Mitochondria from postmitotic cells use O2 at a high rate, hence releasing oxygen radicals that exceed the cellular antioxidant defences. The key role of mitochondria in cell aging has been outlined by the degeneration induced in cells microinjected with mitochondria isolated from fibroblasts of old rats, especially by the inverse relationship reported between the rate of mitochondrial production of hydroperoxide and the maximum life span of species. An important change in mitochondrial lipid composition is the age-related decrease found in cardiolipin content. The concurrent enhancement of lipid peroxidation and oxidative modification of proteins in mitochondria further increases mutations and oxidative damage to mitochondrial DNA (mtDNA) in the aging process. The respiratory enzymes containing the defective mtDNA-encoded protein subunits may increase the production of reactive oxygen species, which in turn would aggravate the oxidative damage to mitochondria. Moreover, superoxide radicals produced during mitochondrial respiration react with nitric oxide inside mitochondria to yield damaging peroxynitrite. Treatment with certain antioxidants, such as sulphur-containing antioxidants, vitamins C and E, or the Ginkgo biloba extract EGb 761, protects against the age-associated oxidative damage to mtDNA and the oxidation of mitochondrial glutathione. Moreover, the EGb 761 extract also prevents changes in mitochondrial morphology and function associated with aging of the brain and liver.
1972年，哈曼首次提出线粒体可能是衰老过程中的生物钟，并指出氧消耗速率应决定自由基反应产生的线粒体损伤的积累速率。1980年晚些时候，米克尔及其同事提出了细胞衰老的线粒体理论。有丝分裂后细胞的线粒体以高速率消耗氧气，因此释放出超过细胞抗氧化防御能力的氧自由基。线粒体在细胞衰老中的关键作用已通过向注射了从老年大鼠成纤维细胞分离的线粒体的细胞中诱导的退化得以阐明，特别是通过线粒体过氧化氢产生速率与物种最大寿命之间报道的反比关系。线粒体脂质组成的一个重要变化是心磷脂含量随年龄的下降。线粒体中脂质过氧化和蛋白质氧化修饰的同时增强进一步增加了衰老过程中线粒体DNA（mtDNA）的突变和氧化损伤。含有缺陷的mtDNA编码蛋白亚基的呼吸酶可能会增加活性氧的产生，这反过来又会加剧线粒体的氧化损伤。此外，线粒体呼吸过程中产生的超氧自由基与线粒体内的一氧化氮反应生成具有破坏性的过氧亚硝酸盐。用某些抗氧化剂进行处理，如含硫抗氧化剂、维生素C和E，或银杏叶提取物EGb 761，可以防止与年龄相关的mtDNA氧化损伤和线粒体谷胱甘肽的氧化。此外，EGb 761提取物还可防止与脑和肝衰老相关的线粒体形态和功能变化。
