Investigation of developmental peroxide generation as an important lifespan-deter

描述(申请人提供)：在遗传和时间上相同的动物在寿命和与衰老相关的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，一种被称为衰老随机性的现象，被认为要么是整个生命周期中随机积累的损害的结果，要么是影响生命早期寿命的发育设定的调节信号的结果。基于我们实验室以前的结果，我们现在将测试这一假设，即在线虫幼虫发育过程中观察到的过氧化氢水平的大幅波动会触发一系列氧化还原控制的事件，从而使寿命个体化，从而导致观察到的寿命变化。长期以来，生物体中的活性氧物种，如过氧化氢，一直被认为是与年龄相关的生理性衰退的原因。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，对新陈代谢、生长和发育产生了积极的影响。我们已经产生了转基因线虫，可以表达比率测定的过氧化氢传感器蛋白。这些传感器蛋白使我们能够实时地和在活的生物体中确定和监测在其生命中任何定义的时间点产生的内源性过氧化氢的相对数量。我们已经发现，线虫在生命早期积累了高水平的过氧化氢，进入成年期后恢复不断减少的环境的能力似乎可以预测寿命，发育中过氧化氢水平低于平均水平的个体表现出更长的寿命。我们现在将使用这些表达过氧化氢传感器的蠕虫来关联个体线虫的内源过氧化氢水平与它们与年龄相关的表型、抗逆性和寿命。我们将根据线虫早期发育的ROS水平对其进行分类，研究与早期生命过氧化物酶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来识别生理上重要的氧化还原敏感靶蛋白。因此，我们的研究有明显的潜力来揭示个体何时产生，并揭示发育产生的活性氧物种决定寿命的机制(S)。

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.