Translational Studies Linking Aging and Cancer

连接衰老和癌症的转化研究

• 批准号: 8611719
• 负责人: CYNTHIA J. KENYON
• 金额: $ 33.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8611719
• 关键词: Age; Aging; Animals; Antineoplastic Agents; Basic Science; Biological; Biology of Aging; Birds; Breast Cancer Cell; Cadmium; Caenorhabditis elegans; Caloric Restriction; Cancer cell line; Cell Aging; Cells; Collaborations; DNA Damage; Development; Diagnostic Neoplasm Staging; Disease; Dose; Dreams; FOXO3A gene; Fibroblasts; Fishes; Gene Mutation; Genes; Gray unit of radiation dose; Growth; Health; Heavy Metals; Human; Hydrogen Peroxide; Insulin-Like Growth Factor I; Knowledge; Lead; Life; Life Stress; Link; Longevity; Longevity Pathway; Malignant - descriptor; Malignant Neoplasms; Mammals; Mus; Mutation; Non-Malignant; Nutrient; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Phenotype; Prodrugs; Proteins; Research Personnel; Resistance; Science; Small Interfering RNA; Stress; Testing; Tissues; adenylate kinase; age related; anticancer activity; combat; cytokine; killings; mutant; neoplastic cell; prevent; public health relevance; receptor; research study; screening; senescence; small molecule; stressor; translational study; tumor growth

DESCRIPTION (provided by applicant): This project employs a new strategy, suggested by basic research in the science of aging, to find small molecules (precursors of drugs) that extend healthy, youthful lifespan and combat age-related diseases such as cancer. In animals, mutations in many nutrient, energy and stress-sensing genes extend youthfulness and lifespan and prevent age-related disease. A shared dream of aging researchers is that these remarkable findings will lead to new ways to keep us more youthful and disease-free as we age. My lab has carried out a small-molecule screen in hopes of bringing this dream closer to reality. Instead of targeting a single aging regulator, we cast a wide net by screening first for a cellular phenotype that is shared by cells from many long-lived animal mutants, as well as cells from long-lived species: increased resistance to multiple forms of environmental stress. When similar screens have been done in animals, a fraction of the hits have proven to extend lifespan. From a screen of 104,000 compounds, we found ~ 50 that make human primary cells in culture resistant to oxidative stress. Some confer resistance to other stressors as well. We are now asking which of these compounds might activate human longevity pathways. So far, at least some small molecules activate pathways that extend lifespan in animals, and at least some appear to increase C. elegans stress resistance and lifespan. A hallmark of many long-lived mutants is cancer resistance, and several of our top hits are predicted to have anticancer activity. Thus this screening strategy may lead to new ways to treat or prevent cancer. We will explore this hypothesis by testing our small molecules for anticancer activity. Relevance: Cancer is an age-related disease, and many gene perturbations that extend lifespan in animals also delay cancer. In this study, we use our knowledge of the basic biology of aging to develop new ways to find drugs against cancer. These drugs should also increase youthfulness and general health.

描述（由申请人提供）：该项目采用一种新的策略，由衰老科学的基础研究提出，寻找小分子（药物的前体），延长健康、年轻的寿命，并对抗与年龄有关的疾病，如癌症。在动物中，许多营养、能量和压力感应基因的突变可以延长青春和寿命，并预防与年龄有关的疾病。衰老研究人员的一个共同梦想是，这些了不起的发现将带来新的方法，让我们随着年龄的增长更年轻，远离疾病。我的实验室已经研制出一种小分子屏幕，希望能让这个梦想更接近现实。我们不是针对单一的衰老调节因子，而是首先筛选许多长寿动物突变体细胞和长寿物种细胞共有的细胞表型：对多种形式的环境压力的抵抗力增强。当在动物身上进行类似的筛选时，一小部分成功的药物被证明可以延长寿命。从104,000种化合物中，我们发现了约50种使培养的人类原代细胞抵抗氧化应激的化合物。有些还能抵抗其他压力源。我们现在想知道，这些化合物中的哪一种可能会激活人类的长寿途径。到目前为止，至少有一些小分子激活了延长动物寿命的途径，至少有一些似乎增加了秀丽隐杆线虫的抗逆性和寿命。许多长寿突变体的一个特点是具有抗癌性，我们的一些热门突变体预计具有抗癌活性。因此这