Metal Homeostasis and Aging

描述(由申请人提供)：在发达国家，老龄化是疾病的最大单一风险因素。美国人口持续的“老龄化”极大地增加了患上社会和经济上重要的年龄相关疾病的人口比例，包括帕金森氏症、阿尔茨海默病和成人癌症[1]。在过去20年中，线虫寿命的遗传修饰物的发现对哺乳动物衰老甚至人类基因研究的许多研究都起到了至关重要的推动作用。这揭示了许多基因，例如那些编码胰岛素信号功能的基因，影响正常寿命，也决定了疾病的病理。然而，我们仍然缺乏对细胞内信号通路如何在生化和代谢水平上影响衰老的全面了解，这表明我们应该寻求在模式生物中研究衰老的新方法。衰老与身体成分的变化和各种动态平衡系统的丧失有关。在线虫模型中，我们观察到随着年龄的增长，金属动态平衡的急剧丧失，并有证据表明，金属丰度的变化调节了寿命。在这里，我们建议了解金属稳态的丧失(金属沉积)对衰老的贡献。我们将确定新的金属淤积调节剂和维持金属淤积、改善健康和延长寿命的小分子。 与公共健康相关：衰老与身体成分的变化以及身体或单个细胞寻求和维持各种基本因素的内部平衡的能力丧失有关。这种与年龄相关的变化的一个例子是金属在各种组织中的积累。这种金属动态平衡(金属滞留)的丧失也是 一些与年龄有关的疾病。我们将在线虫身上测试这一想法，在那里我们可以常规地从遗传学和药理学上操纵衰老。这项研究将导致识别调节金属沉积的基因，以及保持金属沉积以延长健康寿命的小分子。

DESCRIPTION (provided by applicant): Aging is the single largest risk factor for disease in developed countries. The ongoing demographic "aging" of the American population has greatly increased the proportion of the population at risk for socially and economically important age-related diseases including Parkinson's disease, Alzheimer's disease and adult cancers [1]. Discoveries made over the last twenty years on the genetic modifiers of lifespan in the nematode C. elegans have been vital as an impetus for much of the research conducted on mammalian aging and even human genetic studies. This has revealed that many genes, such as those encoding insulin signaling functions, influence normal longevity and also determine disease pathology. However, we still lack an overall understanding of how intracellular signaling pathways influence aging at a biochemical and metabolic level which suggests we should seek new ways of studying aging in model organisms. Aging is associated with changes in body composition and loss of various homeostatic systems. In a nematode model, we have observed a dramatic loss of metal homeostasis with age and have evidence that alterations in metal abundance modulate lifespan. Here we propose to understand the contribution of a loss of metal homeostasis (metallostasis) to aging. We will identify novel regulators of metallostasis and small molecules that maintain metallostasis, improve health and extend lifespan. PUBLIC HEALTH RELEVANCE: Aging is associated with changes in body composition and with a loss of ability by the body or an individual cell to seek and maintain internal balance of various essential factors. An example of such an age-related change is the accumulation of metals in various tissues. This loss of metal homeostasis (metallostasis) is also characteristic of a number of age-related diseases. We will test this idea in C. elegans where we can routinely manipulate aging genetically and pharmacologically. This study will lead to the identification of genes that modulate metallostasis and to small molecules that maintain metallostasis to extend healthy lifespan.