Stochastic aspects of aging (5 of 11)

所有的生物系统都受到随机变化的影响。在哺乳动物中，这一点从体型较大的个体中可见一斑。 寿命的变化和与衰老相关的病理模式，即使在基因相同的动物中也是如此。 随机性在分子水平上也很明显。随机分子波动造成的可变性 在细菌和酵母中已经证明了细胞群体中的基因表达。在某种程度上，这 是信息传递过程的本质所固有的，特别是在少量的信使核糖核酸或 每个细胞的蛋白质产物。然而，分子水平上的噪音也可能有外部原因，不同于 调节信号的可变性对基因组的随机损伤。虽然有时是有利的，即在 发展和进化，在衰老中增加的随机性通常被认为具有有害的影响 关于细胞功能。这一提议的中心假设是氧化应激，这可能是衰老的一个原因， 增加基因表达的随机变异性，这是通过引起遗传和表观遗传来实现的 细胞的变化，以及细胞和生物体拥有各种遗传途径和细胞反应 缓解或缓冲过大的随机变化。我们将通过两个具体的例子来检验这一假设 目标。首先，我们将比较分析四种不同的衰老模型系统，线虫，果蝇，小鼠 和人类细胞，在类似的LacZ报告结构中进行突变积累。我们还将调查如何 这种基因组水平的随机性取决于已知的导致衰老相关的遗传因素 神经退行性疾病，人类和小鼠细胞之间的不同，以及它如何通过 遗传因素。其次，我们将直接测量小鼠神经元和神经元中的转录噪音水平 老化过程中的干细胞和人类神经退行性疾病的模型系统。同时，我们将 研究不同遗传背景的人和小鼠成纤维细胞中相似的转录噪声 在老化过程中的个体线虫之间。我们期望拟议的研究将提供一个新的层面。 通过定义随机性在衰老表型中的作用并确定 影响它的遗传和生化机制。

All biological systems are subject to stochastic variation. In mammals this is obvious from the large individual variation in life span and patterns of aging-related pathology, even in genetically homogeneous animals. Stochasticity is also apparent at the molecular level. Random molecular fluctuations creating variability in gene expression within a cell population have been demonstrated in bacteria and yeast. To some extent this is inherent to the nature of the processes of information transfer, especially at small numbers of mRNA or protein products per cell. However, noise at the molecular level can also have external causes, varying from random damage to the genome to variability in regulatory signals. While sometimes advantageous, i.e., in development and evolution, increased Stochasticity in aging is generally viewed as having detrimental effects on cellular function. The central hypothesis in this proposal is that oxidative stress, a likely cause of aging, increases stochastic variability of gene expression, that it does so by causing both genetic and epigenetic changes in cells, and that cells and organisms possess a variety of genetic pathways and cellular responses to mitigate or buffer against unduly large stochastic changes. We will test this hypothesis in two specific aims. First, we will comparatively analyze four different model systems of aging, nematodes, fruit flies, mice and human cells, for mutation accumulation at a similar lacZ reporter construct. We will also investigate how such genome level Stochasticity depends on genetic factors known to cause aging-related neurodegenerative disease, how it differs between human and mouse cells and how it can be modulated by genetic factors. Second, we will directly measure transcriptional noise levels in mouse neurons and neuronal stem cells during aging and in model systems for human neurodegenerative diseases. In parallel, we will study similar transcriptional noise in human and mouse fibroblasts in different genetic backgrounds and among individual nematodes during aging. We expect that the proposed study will provide a new dimension to existing paradigms in the field by defining the role of Stochasticity in aging phenotypes and identifying the genetic and biochemical mechanisms that influence it.