Metal Homeostasis and Aging

金属稳态和老化

• 批准号: 8285984
• 负责人: Gordon J Lithgow
• 金额: $ 30.49万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8285984
• 关键词: Address; Adult; Age; Aging; Aging-Related Process; Alzheimer' s Disease; American; Animal Model; Attenuated; Binding; Biochemical; Body Composition; Caenorhabditis elegans; Calcium; Cells; Characteristics; Clioquinol; Copper; Coupled; Demographic Aging; Developed Countries; Development; Disease; Elements; Equilibrium; Genes; Genetic; Health; Homeostasis; Human; Human Genetics; Individual; Induced Mutation; Investigation; Iron; Laboratories; Lead; Life; Lithium; Location; Longevity; Magnesium; Malignant Neoplasms; Metabolic; Metals; Minerals; Modeling; Mutation; Nematoda; Optics; Organism; Parkinson Disease; Pathology; Pattern; Phenotype; Plasma; Population; Populations at Risk; Prevention; RNA Interference; Regulation; Research; Research Personnel; Risk Factors; Signal Pathway; Staging; System; Testing; Therapeutic; Tissues; Toxic effect; Variant; Zinc; age related; design; dopaminergic neuron; experience; healthy aging; improved; insulin signaling; interest; juvenile animal; mutant; neuron loss; normal aging; novel; prevent; skills; small molecule; tool

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.

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。美国人口持续的人口“老龄化”大大增加了面临社会和经济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[1]。过去二十年来，关于线虫寿命基因修饰剂的发现对于哺乳动物衰老甚至人类基因研究的大部分研究起到了至关重要的推动作用。这表明许多基因，例如编码胰岛素信号功能的基因，影响正常寿命并决定疾病病理。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影响衰老的全面了解，这表明我们应该寻求研究模型生物衰老的新方法。衰老与身体成分的变化和各种稳态系统的丧失有关。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变化会调节寿命。在这里，我们建议了解金属稳态（金属稳态）丧失对衰老的影响。我们将找到新的金属稳态调节剂和维持金属稳态、改善健康和延长寿命的小分子。 公共卫生相关性：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重要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。这种金属稳态（金属稳态）的丧失也是 一些与年龄有关的疾病。我们将在秀丽隐杆线虫中测试这个想法，在那里我们可以常规地通过遗传和药理学来操纵衰老。这项研究将鉴定调节金属稳态的基因和维持金属稳态以延长健康寿命的小分子。