Metal Homeostasis and Aging

描述（由申请人提供）：在发达国家，衰老是疾病的最大单一风险因素。美国人口的持续“老龄化”大大增加了面临社会和经济上重要的年龄相关疾病风险的人口比例，包括帕金森病、阿尔茨海默病和成人癌症。在过去的二十年里，关于秀丽隐杆线虫寿命的遗传修饰因子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。这表明，许多基因，如编码胰岛素信号功能的基因，影响正常寿命，也决定疾病病理。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理解，这表明我们应该寻求新的方法来研究模式生物的衰老。衰老与身体组成的变化和各种体内平衡系统的丧失有关。在线虫模型中，我们观察到金属稳态随着年龄的增长而急剧丧失，并有证据表明金属丰度的改变可以调节寿命。在这里，我们建议了解金属稳态（金属稳态）的损失对衰老的贡献。我们将发现新的金属平衡调节因子和维持金属平衡、改善健康和延长寿命的小分子。

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.