METABOLIC MECHANISMS LIMITING AND PROTECTING LONGEVITY

描述（由申请人提供）：本项目将在一系列实验系统中测试与长寿和代谢损伤控制有关的途径和机制。应该通过研究比较代谢来确定限制或减少各种广泛不同的分类群寿命的共同因素。我们将寻求共同的“代谢指纹”预测生存在不同的模型老化系统，使用一套强大的诊断工具。PROJECT 1利用功能标准来确定线虫寿命和抗病性的新遗传决定因素，测试这些功能存在于相同基因中的假设。这些基因将与14种长寿突变菌株和两种延长寿命的饮食方式进行比较，以了解对呼吸和代谢谱的影响。项目2测试了同一假设的一个特定预测，即已知的抗氧化系统-高度专门用于去除脂质过氧化产物的GST酶的一个分支-应该延长果蝇和线虫的寿命并增强对氧化应激的抵抗力。项目3通过比较不同年龄的大鼠和小鼠的氧化损伤和代谢状态的测量，解决了神经元代谢在衰老和寿命中的核心作用，+/-氧化应激，作为两种长寿改变方案之一的结果：热量限制或表观遗传修饰。PROJECT 4测试了一个假设，即寿命可以通过小鼠基因表达的表观遗传改变来延长，这种改变要么是通过母体饮食的短暂改变，要么是通过一种必需DNA甲基转移酶的杂合突变引起的。项目5检查酵母线粒体呼吸功能、生物能量学和损伤，测试呼吸控制是否决定活性氧的产生和酵母寿命，并试图通过呼吸状态的遗传扰动来调节酵母、蠕虫和苍蝇的寿命。代谢评估CORE将测量代谢途径、活动和终生输出的多个指标；抗氧化防御状况；以及稳定状态和应激后潜在有害代谢副产物的水平。因此，在每个系统的配对比较中，我们将测试代谢损伤模型的一个关键预测：任何年龄的预期未来生存，取决于当前大分子损伤的状态，加上新损伤的累积率——这反过来反映了抗氧化防御和自由基代谢生成之间的平衡。通过在几个模型系统中发现指示长寿的代谢模式，我们可以确定那些最有可能与人类衰老和年龄依赖性疾病相关的代谢模式。

DESCRIPTION (provided by applicant): This Program Project will test pathways and mechanisms implicated in the control of longevity and metabolic damage, for a range of experimental systems. Shared factors that limit or reduce longevity in a variety of widely divergent taxa should be identifiable by studying comparative metabolism. We will seek common "metabolic fingerprints" predicting survival in diverse model aging systems, using a single set of powerful diagnostic tools. PROJECT 1 utilizes functional criteria to identify new genetic determinants of longevity and stress resistance in C. elegans, testing the hypothesis that these functions reside in the same genes. These genes will be compared to 14 long-lived mutant strains and two dietary means of life-extension, for effects on respiration and metabolic profiles. PROJECT 2 tests a specific prediction of the same hypothesis, that a known antioxidant system--a subset of GST enzymes highly specialized for removal of lipoperoxidation products should extend longevity and enhance resistance to oxidative stress in both fruit flies and nematodes. PROJCT 3 addresses the central role of neuronal metabolism to aging and life span, by comparing measures of oxidative damage and of metabolic status in rats and mice of varying age, +/- oxidative stress, as a consequence of either of two longevity-altering regimens: caloric restriction or epigenetic modification. PROJECT 4 tests the hypothesis that longevity can be extended through epigenetic alteration of gene expression in the mouse--elicited either by transient modification of the maternal diet or by heterozygous mutation to an essential DNA methyltransferase. PROJECT 5 examines yeast mitochondrial respiratory functions, bioenergetics, and damage, testing whether respiratory control determines generation of reactive oxygen species and yeast longevity, and attempting to modulate life span of yeast, worms, and flies by genetic perturbation of the respiratory state. The METABOLIC ASSESSMENT CORE will measure multiple indicators of metabolic pathways, activity and lifetime output; status of antioxidant defenses; and the steady state and post -stress levels of potentially damaging metabolic byproducts. Thus, in paired comparisons for each system, we will test a key prediction of the metabolic-damage model: expected future survival at any age, depends on the current status of macromolecular damage, plus the rate of accrual of new damage -- which in turn reflects the balance between antioxidant defenses and the metabolic generation of free radicals. By finding metabolic patterns that are indicative of longevity in several model systems, we can determine those most likely to be relevant to human aging and age-dependent disease.