Pharmacology of Lifespan Extension

描述(由申请人提供)：本提案是对《2009年美国复苏和再投资法案》(ARRA)和NOT-OD-09-058的回应。在发达国家，老龄化是疾病的单一最大风险因素。美国人口正在发生的人口变化极大地增加了社会和经济上与年龄相关的重要疾病的风险比例，包括帕金森氏病(PD)、阿尔茨海默氏症和癌症。与年龄相关的疾病可以说是21世纪生物医学面临的最大挑战。与年龄相关的疾病越来越多地代表着国家紧急状态；这可能会破坏《美国复苏和再投资法案》(ARRA)的中期利益。这份补充申请通过创造两个就业机会并提议从美国科学供应商那里购买用品和设备来实现ARRA的目标。受我们之前发现的可以延长寿命和抵御压力的化合物的推动，我们在父母拨款中提议寻找新的化合物来减缓线虫的衰老速度，并确定其作用机制。我们期待这样的工作将为年龄相关疾病的治疗方法的发展开辟新的途径。我们有了一个惊人的发现，一组通常用于在神经系统疾病中染色聚集蛋白的化合物延长了线虫的正常寿命。此外，我们发现有证据表明，这些化合物，特别是硫代黄素T(THT)正在减缓体内蛋白质聚集体的形成。这些化合物以前曾用于人体临床研究。我们之前发现，锂通常被用作治疗双相情感障碍的药物，可以延长线虫的寿命。我们认为锂通过一种独特的机制起作用，涉及表观遗传修饰。我们现在建议扩大赠款的范围，以调查这两种有趣的干预措施所起的作用机制。目前遵循这两条线索是很重要的，因为它们似乎通过不同的机制发挥作用。通过探索两种可能的延缓衰老的机制，我们更有可能找到对人类衰老和与年龄相关的疾病具有重要意义的干预措施。由于锂已经是一种广泛使用的药物，而且已经在临床研究中使用，这一提议将导致衰老方面的翻译研究的可能性似乎很高。 公共卫生相关性：这一要求与美国复苏和再投资法案(ARRA)直接相关，因为它呼吁创造新的就业机会，并从美国公司购买科学设备和用品。它还涉及经济上重要的年龄相关疾病的治疗方法的发展，并直接涉及“健康跨度”，这是老龄生物学司的一项战略优先事项。

DESCRIPTION (provided by applicant): This proposal is in response to the American Recovery and Reinvestment Act 2009(ARRA) and to NOT-OD-09-058. Aging is the single largest risk factor for disease in developed countries. The ongoing demographic change in the American population is greatly increasing the proportion of the population at risk for socially and economically important age-related diseases including Parkinson's disease (PD), Alzheimer's disease and cancer. Age-related disease is arguably the single greatest challenge for biomedicine in the 21st Century. Age-related diseases increasingly represent a national emergency; one that may undermine the mid-term benefits of the American Recovery and Reinvestment Act (ARRA). This supplement application addresses the goals of the ARRA by creating two job opportunity and proposing to purchase supplies and equipment from American scientific suppliers. Prompted by our prior discovery of compounds which extend lifespan and protect against stress we proposed in the parent grant to find new compounds that slow aging rates of the nematode C. elegans and determine the mechanisms at play. We expected such work to open new avenues for development of therapeutics for age-related diseases. We have made the striking discovery that a group of compounds commonly used to stain aggregating proteins in neurological disease increase the normal lifespan of C. elegans. Moreover, we find evidence that the compounds, especially thioflavin T (ThT) are slowing in vivo protein aggregate formation. The compounds have been previously used in human clinical studies. We previously discovered that Lithium, commonly used as a drug for the treatment of bipolar disorder, extends C. elegans lifespan. We believe Lithium acts via a distinct mechanism involving epigenetic modifications. We now propose to extend the scope of the grant to investigate the mechanisms at play for both these interesting interventions. It is important to follow BOTH leads at this time because it appears they act by different mechanisms. By pursuing two potential mechanisms to slow aging, we are more likely to find an intervention with significance to human aging and age-related disease. Since Lithium is already a drug in widespread use and ThT has been used in clinical research the likelihood that this proposal will lead to translational research in aging appears high. PUBLIC HEALTH RELEVANCE: This request is directly relevant to American Recovery and Reinvestment Act (ARRA) as it calls for the creation of a new job opportunity and the purchase of scientific equipment and supplies from American companies. It also addresses the development of therapeutics for economically important age-related diseases and it directly addresses "healthspan", a strategic priority for the Division of Aging Biology.