Investigation of developmental peroxide generation as an important lifespan-deter

描述（由申请人提供）：基因上和时间上相同的动物在寿命和衰老相关病理的随机模式上表现出惊人的巨大差异。这种明显的随机性，一种被称为衰老的随机性的现象，被认为是由于整个生命周期中损伤的随机积累和/或来自发育设定的调节信号，这些信号在生命早期影响寿命。基于我们实验室之前的结果，我们现在将验证这样一个假设，即在秀丽隐杆线虫幼虫发育过程中观察到的过氧化氢水平的大幅波动触发了一系列氧化还原控制的事件，这些事件使寿命个性化，从而导致了观察到的寿命变化。活性氧，如过氧化物，长期以来一直被认为有助于生物体与年龄相关的生理衰退。然而，最近的研究也揭示了活性氧作为细胞内信号分子的调节作用，积极影响代谢、生长和发育。我们已经产生了转基因秀丽隐杆线虫，表达比例过氧化物传感器蛋白。这些传感器蛋白使我们能够实时测定和监测活生物体在其生命中任何特定时刻产生的内源性过氧化物的相对量。我们已经发现秀丽隐杆线虫在生命早期积累了高水平的过氧化物，进入成年后恢复还原环境的能力似乎预示着长寿，并且低于平均发育水平的过氧化物水平的个体显示出更长的寿命。我们现在将使用这些表达过氧化物传感器的蠕虫，将单个秀丽隐杆线虫的内源性过氧化物水平与其年龄相关的表型、抗逆性和寿命联系起来。我们将根据线虫发育早期的ROS水平对其进行分类，研究与早期活性氧水平相关的基因表达谱，并应用靶向氧化还原-蛋白质组学技术鉴定生理上重要的氧化还原敏感靶蛋白。因此，我们的研究有明确的潜力揭示个性何时产生，并揭示发育过程中产生的活性氧决定寿命的机制。

DESCRIPTION (provided by applicant): Genetically and chronologically identical animals show surprisingly large variations in lifespan and random patterns of aging-related pathologies. This apparent randomness, a phenomenon known as stochasticity of aging, is thought to either result from stochastic accumulation of damage over the entire lifespan and/or from developmentally set regulatory signals, which affect lifespan early in life. Based on previous results from our lab, we will now test the hypothesis that large fluctuations in peroxide levels observed during the larval development of C. elegans trigger a chain of redox-controlled events that individualize lifespan, thereby contributing to the observed lifespan variability. Reactive oxygen species, such as peroxide, have long been postulated to contribute to the age-associated physiological decline in organisms. More recent studies, however, also revealed regulatory roles of reactive oxygen species as intracellular signaling molecules, positively affecting metabolism, growth and development. We have generated transgenic C. elegans, which express ratiometric peroxide sensor proteins. These sensor proteins allow us to determine and monitor in real- time and in live organisms the relative amount of endogenous peroxide produced at any defined point in their life. We have discovered that C. elegans accumulate high levels of peroxide early in life, that the ability to restore a reducing environmen upon entering adulthood appears to predict longevity, and that individuals with lower than average developmental peroxide levels show an extended lifespan. We will now use these peroxide sensor-expressing worms to correlate endogenous peroxide levels in individual C. elegans with their age-related phenotypes, stress resistance and lifespan. We will sort C. elegans according to their ROS levels in early development, investigate the gene expression profile associated with variable early-life peroxide levels and apply targeted redox-proteomic techniques to identify physiologically important redox sensitive target proteins. Our studies have therefore the clear potential to reveal when individuality arises and uncover the mechanism(s) by which developmentally produced reactive oxygen species determine lifespan.