Metabolome-Genome Associations for Determining Mechanisms of Aging in Drosophila

 描述(申请人提供)：为什么我们会变老，为什么有些人变老得比其他人快？遗传学研究发现了许多可以在实验室种群中延长寿命的基因。然而，这些基因几乎解释不了人类的实质性遗传变异。 我们在自然人口中观察到的寿命，包括人类。环境研究发现，饮食限制(DR)可以延长寿命，而且这种影响在不同的类群中高度保守。然而，在种群内，DR反应显示出相当大的遗传变异。与寿命一样，解释DR反应中这种遗传差异的途径也是未知的。我们的首要目标是了解在衰老过程中形成这种自然变异的遗传途径、作用机制和选择性力量。为此，我们收集了三组重要的初步数据。首先，我们发现性别、饮食、组织类型、基因和年龄都对果蝇的代谢物有实质性的影响。 其次，饮食限制可以延长平均寿命，导致AGE对代谢物的影响发生戏剧性逆转，这种逆转似乎与糖原、葡萄糖和色氨酸代谢有关。第三，饮食限制延长了一些基因类型的寿命，而在另一些基因类型中则根本没有反应。基于这些数据，我们假设，延长寿命的遗传和环境因素主要是通过减缓代谢途径中与年龄相关的变化来实现的，这些途径的变化将使我们能够a)预测基因的寿命；b)预测给定基因的寿命是否会对DR做出反应；以及c)发现DR延长寿命的机制。具体地说，我们假设DR将通过减缓与年龄相关的变化来延长寿命，这些变化与导致寿命自然变化的分子途径相同。我们将通过对衰老速度有显著差异的种群中的代谢组进行基因定位，并通过确定决定个体基因类型如何对DR做出反应的因果代谢途径来检验我们的假设。最后，我们将利用果蝇遗传学的力量来操纵果蝇的代谢物水平和基因表达。这些操作将使我们能够测试从我们的初步研究和这里提出的工作产生的结果中产生的特定机械假说。这种创新的方法将高度敏感的代谢组学与定量和分子遗传学结合在一个易于操作的模型生物体中，使我们能够以前所未有的规模和详细程度了解衰老和与衰老相关的扰动的自然变异背后的分子机制。这项工作有望为深入研究因素延长寿命的作用机制提供关键的见解，并有助于更清楚地理解自然种群中适应性特征的变异是如何产生和维持的。这里提出的代谢组谱也可以很容易地在人类群体中进行，因此，我们的方法有长期潜力来揭示与人类衰老和年龄相关疾病相关的分子途径。

 DESCRIPTION (provided by applicant): Why do we age, and why do some individuals age faster than others? Genetic studies have found many genes that can extend lifespan in laboratory populations. However, these genes explain little of the substantial genetic variation in lifespan that we observe in natural populations, including humans. Environmental studies have found that diet restriction (DR) can extend lifespan, and that this effect is highly conserved across taxa. However, within populations, the DR response shows considerable genetic variation. As with lifespan, the pathways that account for this genetic variation in the DR response are also unknown. Our overarching goal is to understand the genetic pathways, functional mechanisms and selective forces that shape this natural variation in aging. Towards this end, we have gathered three important sets of preliminary data. First, we have found that sex, diet, tissue type, genotype, and age all have substantial effects on the fruit fly metabolome. Second, diet restriction, which can extend mean lifespan, leads to a dramatic reversal of the effect of age on the metabolome, and this reversal appears to be associated with glycogen, glucose, and tryptophan metabolism. Third, diet restriction extends lifespan in some genotypes, while in others there is no response at all. Based on these data, we hypothesize that genetic and environmental factors that extend lifespan do so predominantly by slowing age-related changes in metabolic pathways, and that variation in these pathways will allow us to a) predict the longevity of a genotype; b) predict whether lifespan in a given genotype will respond to DR; and c) discover the mechanisms through which DR extends lifespan. Specifically, we hypothesize that DR will extend lifespan by slowing age-related changes in the same molecular pathways that account for natural variation in longevity. We will test our hypotheses by genetically mapping the metabolome in a population that shows significant variation in rates of aging, and by identifying the causal metabolic pathways that determine how individual genotypes respond to DR. Finally, we will take advantage of the power of fly genetics to manipulate metabolite levels and gene expression in flies. These manipulations will allow us to test specific mechanistic hypotheses that arise from our preliminary studies and from results generated by the work proposed here. This innovative approach combines highly sensitive metabolomic profiling with both quantitative and molecular genetics in an easily manipulated model organism, allowing us to understand the molecular mechanisms that underlie natural variation for aging and aging-related perturbations at an unprecedented scale and level of detail. This work is expected to provide critical insights into the functional mechanisms by which well-studied factors increase lifespan, and to lead to a clearer understanding of how variation in fitness traits is generated and maintained in natural populations. The metabolomic profiling proposed here can also be carried out easily in human populations, and as such, our approach has the long- term potential to reveal the molecular pathways associated with aging and age-related disease in humans.