Flores Lisa C, Ortiz Melanie, Dube Sara, Hubbard Gene B, Lee Shuko, Salmon Adam, Zhang Yiqiang, Ikeno Yuji
Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA ; Department of Pathology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
Longev Healthspan. 2012 Sep 3;1:4. doi: 10.1186/2046-2395-1-4. eCollection 2012.
The Free Radical or Oxidative Stress Theory of Aging is one of the most popular theories in aging research and has been extensively studied over the past several decades. However, recent evidence using transgenic/knockout mice that overexpress or down-regulate antioxidant enzymes challenge the veracity of this theory since the animals show no increase or decrease in lifespan. These results seriously call into question the role of oxidative damage/stress in the aging process in mammals. Therefore, the theory requires significant modifications if we are to understand the relationship between aging and the regulation of oxidative stress. Our laboratory has been examining the impacts of thioredoxins (Trxs), in the cytosol and mitochondria, on aging and age-related diseases. Our data from mice that are either up-regulating or down-regulating Trx in different cellular compartments, that is, the cytosol or mitochondria, could shed some light on the role of oxidative stress and its pathophysiological effects. The results generated from our lab and others may indicate that: 1) changes in oxidative stress and the redox state in the cytosol, mitochondria or nucleus might play different roles in the aging process; 2) the role of oxidative stress and redox state could have different pathophysiological consequences in different tissues/cells, for example, mitotic vs. post-mitotic; 3) oxidative stress could have different pathophysiological impacts in young and old animals; and 4) the pathophysiological roles of oxidative stress and redox state could be controlled through changes in redox-sensitive signaling, which could have more diverse effects on pathophysiology than the accumulation of oxidative damage to various molecules. To critically test the role of oxidative stress on aging and age-related diseases, further study is required using animal models that regulate oxidative stress levels differently in each cellular compartment, each tissue/organ, and/or at different stages of life (young, middle and old) to change redox sensitive signaling pathways.
衰老的自由基或氧化应激理论是衰老研究中最流行的理论之一，在过去几十年中得到了广泛研究。然而，最近使用过表达或下调抗氧化酶的转基因/基因敲除小鼠的证据对该理论的真实性提出了挑战，因为这些动物的寿命并未增加或减少。这些结果严重质疑了氧化损伤/应激在哺乳动物衰老过程中的作用。因此，如果我们要理解衰老与氧化应激调节之间的关系，该理论需要进行重大修改。我们实验室一直在研究细胞质和线粒体中的硫氧还蛋白（Trxs）对衰老和与年龄相关疾病的影响。我们从在不同细胞区室（即细胞质或线粒体）中上调或下调Trx的小鼠获得的数据，可能会揭示氧化应激的作用及其病理生理效应。我们实验室和其他实验室得出的结果可能表明：1）细胞质、线粒体或细胞核中氧化应激和氧化还原状态的变化在衰老过程中可能发挥不同作用；2）氧化应激和氧化还原状态的作用在不同组织/细胞中可能产生不同的病理生理后果，例如有丝分裂细胞与后有丝分裂细胞；3）氧化应激在幼年和老年动物中可能产生不同的病理生理影响；4）氧化应激和氧化还原状态的病理生理作用可以通过氧化还原敏感信号的变化来控制，这对病理生理学的影响可能比各种分子氧化损伤的积累更为多样。为了严格检验氧化应激对衰老和与年龄相关疾病的作用，需要使用在每个细胞区室、每个组织/器官和/或生命不同阶段（幼年、中年和老年）以不同方式调节氧化应激水平的动物模型进行进一步研究，以改变氧化还原敏感信号通路。
