Oxidative stress and telomere maintenance in vivo

衰老生物学中的基本问题是--为什么人类会变老？为了回答这个问题，人们提出了许多假设。其中有关于衰老的“氧化损伤理论”和“端粒理论”。“氧化损伤理论”指出，衰老的发生，部分是因为正常的生物过程会释放出能破坏细胞成分的活性氧物种。“端粒理论”指出，衰老的发生部分是因为不表达端粒酶的身体细胞中的每个细胞分裂时都会发生端粒侵蚀。这种端粒序列的丢失最终会导致细胞功能障碍。提出的这项研究旨在澄清一个与这两种“理论”相关的简单问题：体内氧化应激是否会导致端粒序列丢失？这个问题试图统一衰老的“端粒理论”和“氧化损伤理论”--氧化应激可能通过影响端粒序列丢失率来影响与年龄相关的变化。这是一个看似简单的问题，但考虑到测试该问题的各个实验系统的局限性，回答起来并不简单。尽管许多研究表明，在体外组织培养的细胞中，端粒重复序列的丢失速度取决于外源性氧化应激的水平，但这些发现对体内发生的过程的意义尚不清楚。在这里提出的研究中，基因操纵的小鼠将被用来在体内测试这些发现的意义。将培育出锰超氧化物歧化酶基因杂合子和端粒酶RNA缺失纯合子的小鼠队列，并将确定这些队列中相对于适当对照的端粒损失率。通过研究同样缺乏Werner综合征基因的小鼠的端粒序列丢失率，也将确定Werner综合征基因产物在这一过程中的作用。

The fundamental question in the biology of aging is-why do humans age? Many hypotheses have been put forth to answer this question. Among these are "oxidative damage theories" and "telomere theories" of aging. "Oxidative damage theories" state that aging occurs, in part, because normal biologic processes release reactive oxygen species that can damage cellular components. "Telomere theories" state that aging occurs that aging occurs in part, because telomere erosion occurs with each cell division in body cells that don't express telomerase. This loss of telomere sequence results in eventual cellular dysfunction. The research proposed is designed to clarify a simple question related to both of these "theories"does oxidative stress contribute to telomere sequence loss in vivo? This question attempts to unite "telomere theories" and "oxidative" damage theories" of aging-oxidative stress may influence age associated changes through an effect on the rate of telomere sequence loss. A seemingly simple question, it has not been simple to answer given the limitations of the individual experimental systems in which the question has been tested. Although a number of studies have demonstrated an accelerated rate of loss of telomeric repeats dependent on the level of exogenous oxidative stress in cells grown in tissue culture in vitro, the significance of these findings to processes occurring in vivo has been unclear. In the studies proposed herein, genetically manipulated mice will be used to test the significance of these findings in vivo. Mice cohorts heterozygous for the manganese superoxide dismutase gene and homozygous for telomerase RNA deletion will be bred, and rates of telomere loss in these cohorts relative to appropriate controls will be determined. By studying rates of telomere sequence loss in mice also lacking the Werner syndrome gene, the role of the Werner syndrome gene product in this process also will be determined.