METABOLIC MECHANISMS LIMITING AND PROTECTING LONGEVITY

描述(由申请者提供)：该计划项目将为一系列实验系统测试与控制寿命和代谢损伤有关的途径和机制。通过对比较新陈代谢的研究，应该可以确定在各种广泛差异的分类群中限制或缩短寿命的共同因素。我们将使用一套功能强大的诊断工具，在不同的模型衰老系统中寻找预测存活率的共同“代谢指纹”。项目1利用功能标准来确定线虫寿命和抗逆性的新遗传决定因素，测试这些功能驻留在相同基因中的假设。这些基因将与14个长寿突变菌株和两种延长寿命的饮食方式进行比较，以确定对呼吸和新陈代谢的影响。项目2测试了同一假设的具体预测，即已知的抗氧化系统--一种高度专门用于清除脂质过氧化产物的GST酶的子集--应该会延长果蝇和线虫的寿命，并增强对氧化应激的抵抗力。PROJCT 3阐述了神经元代谢对衰老和寿命的核心作用，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，/-氧化应激，作为两种改变寿命的方案之一的结果：限制热量或表观遗传修饰。项目4测试了这样一种假设，即可以通过表观遗传改变小鼠的基因表达来延长寿命--这种改变要么是由母亲饮食的短暂改变引起的，要么是由一种基本的DNA甲基转移酶的杂合突变引起的。项目5检查酵母线粒体的呼吸功能、生物能量学和损伤，测试呼吸控制是否决定了活性氧物种的产生和酵母的寿命，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。代谢评估核心将衡量代谢途径、活动和寿命产出的多个指标；抗氧化剂防御状态；以及潜在破坏性代谢副产物的稳定状态和压力后水平。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存活率取决于大分子损伤的当前状态，加上新损伤的累积率--这反过来反映了抗氧化剂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找到指示寿命的代谢模式，我们可以确定最有可能与人类衰老和年龄相关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.