Metabolome-Genome Associations for Determining Mechanisms of Aging in Drosophila

 描述（由申请人提供）：为什么我们会衰老，为什么有些人比其他人衰老得更快？遗传学研究已经在实验室人群中发现了许多可以延长寿命的基因。然而，这些基因几乎不能解释人类基因组中大量的遗传变异。 包括人类在内的自然种群的寿命。环境研究发现，饮食限制（DR）可以延长寿命，并且这种效果在分类群中高度保守。然而，在人群中，DR反应显示出相当大的遗传变异。与寿命一样，DR反应中这种遗传变异的途径也是未知的。我们的首要目标是了解遗传途径，功能机制和选择力，塑造这种自然变化的老化。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、基因型和年龄都对果蝇代谢组有实质性影响。 第二，饮食限制可以延长平均寿命，导致年龄对代谢组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，饮食限制在某些基因型中延长了寿命，而在其他基因型中根本没有反应。基于这些数据，我们假设延长寿命的遗传和环境因素主要通过减缓代谢途径中与年龄相关的变化来实现，并且这些途径中的变化将使我们能够a）预测基因型的寿命; B）预测给定基因型的寿命是否会对DR做出响应;以及c）发现DR延长寿命的机制。具体来说，我们假设DR将通过减缓与年龄相关的变化来延长寿命，这些变化与寿命自然变化的分子途径相同。我们将测试我们的假设，通过遗传映射的代谢组在人口中，显示显着的变化率的老化，并确定因果代谢途径，确定如何个别基因型响应DR。最后，我们将利用苍蝇遗传学的力量来操纵代谢物水平和基因表达的苍蝇。这些操作将使我们能够测试从我们的初步研究和本文提出的工作产生的结果中产生的特定机制假设。这种创新的方法将高度敏感的代谢组学分析与易于操作的模式生物中的定量和分子遗传学相结合，使我们能够以前所未有的规模和细节水平了解衰老和衰老相关扰动的自然变异的分子机制。这项工作预计将提供关键的洞察功能机制，充分研究的因素增加寿命，并导致更清楚地了解如何在健身性状的变化是产生和维持在自然种群。本文提出的代谢组学分析也可以在人群中容易地进行，因此，我们的方法具有揭示与人类衰老和年龄相关疾病相关的分子途径的长期潜力。

 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.