Human Gene Knockdowns that May Extend Lifespan

人类基因敲除可延长寿命

• 批准号: 8273814
• 负责人: CYNTHIA J. KENYON
• 金额: $ 31.67万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8273814
• 关键词: Affect; Animal Model; Animals; Autophagocytosis; Bioinformatics; Caenorhabditis elegans; Cell Line; Cells; Cellular Assay; Centenarian; Characteristics; Cultured Cells; DNA; Databases; Disease; Drug Delivery Systems; FOXO3A gene; Family; Future; Gene Expression; Genes; Genetic; Genetic Screening; Goals; Health; Heart Diseases; Heat-Shock Response; Human; IGF1 gene; Insulin; Insulin-Like Growth Factor I; Life; Life Extension; Link; Literature; Longevity; Longevity Pathway; Malignant Neoplasms; MicroRNAs; Neurodegenerative Disorders; Nutrient; Orthologous Gene; Oxidative Stress; Pathway interactions; Phenotype; Phosphotransferases; Property; Proteins; Resistance; Role; Serotonin; Signal Transduction; Small Interfering RNA; Stress; Testing; Time; Variant; Xenobiotics; adenylate kinase; age related; base; genome-wide; knock-down; longevity gene; member; mutant; offspring; receptor; response; sensor; stressor; transcription factor

DESCRIPTION (provided by applicant): FOXO transcription factors extend lifespan and delay age-related disease in animals, and many studies have now linked FOXO3A DNA variants to exceptional longevity in humans. Thus, the time seems right to look for human genes that are likely to regulate FOXO-dependent, or other, longevity pathways. FOXO proteins can be activated in many ways to extend animal lifespan. For example, C. elegans FOXO can promote longevity in response to reduced insulin/IGF-1 signaling, altered serotonin signaling, and elevated AMP kinase activity, elevated heat-shock factor activity, elevated lin-4 microRNA activity, elevated Jun kinase activity and other inputs. Thus, there could be many gene perturbations that can extend healthy lifespan in humans; and some of these perturbations may be safer and more effective than others. Because it is not possible to do genetic screens for long-lived humans, we are doing genetic screens in human cells instead. Our experimental strategy is based on the observation that all FOXO- dependent life-extending pathways tested so far (as well as many other life-extension pathways) increase resistance to oxidative stress. Although the role of oxidative stress resistance in life extension is not clear, the correlation is tight enough that in many model organisms, screens for oxidative stress resistance have yielded long-lived mutants. Therefore, to obtain a set of potential human longevity genes, the Kenyon lab has carried out a genome-wide siRNA screen for oxidative stress resistance in a human primary cell line. The gene hits include known C. elegans FOXO regulators, regulators of other longevity proteins such as TOR and NRF2, and new genes as well. From this set, the Kenyon lab will identify good candidates for new human longevity and healthspan genes. To do this, they will determine which knockdowns trigger other correlates of longevity, such as xenobiotic resistance or autophagy. In addition, they will ask which knockdowns perturb the activities of FOXO3A, TOR or NRF2. Finally, to link these genes to longevity, they will test for their ability to influence lifespan in C. elegans and for their altered expression in centenarian families. This fresh approach will define new potential drug targets for extending the youthful and productive years of human life, and for delaying age-related diseases such as cancer, heart disease and/or neurodegenerative disease. PUBLIC HEALTH RELEVANCE: The wonderful finding that changing specific genes can extend healthy lifespan and counteract age- related diseases in animals makes a search for human longevity genes imperative. This study takes a fresh approach, by looking for genes that, when altered, give cultured cells from human's properties characteristic of cultured cells from healthy, long-lived animal mutants and from very long-lived animal species. This study will define new entry points for extending the youthful and productive years of human life, and for delaying age-related diseases such as cancer, heart disease and neurodegenerative disease.

描述（由申请人提供）：FOXO转录因子延长动物的寿命并延缓与年龄相关的疾病，许多研究现已将FOXO 3A DNA变异与人类的异常长寿联系起来。因此，寻找可能调节FOXO依赖性或其他长寿途径的人类基因的时机似乎是正确的。FOXO蛋白可以通过多种方式激活以延长动物寿命。例如，C.线虫FOXO可响应于降低的胰岛素/IGF-1信号传导、改变的5-羟色胺信号传导和升高的AMP激酶活性、升高的热休克因子活性、升高的lin-4 microRNA活性、升高的Jun激酶活性和其它输入而促进长寿。因此，可能有许多基因干扰可以延长人类的健康寿命;其中一些干扰可能比其他干扰更安全、更有效。 因为不可能对长寿的人类进行基因筛查，所以我们在人类细胞中进行基因筛查。我们的实验策略是基于这样的观察，即迄今为止测试的所有FOXO依赖性生命延长途径（以及许多其他生命延长途径）都增加了对氧化应激的抵抗力。虽然抗氧化应激在延长寿命中的作用尚不清楚，但其相关性是 在许多模式生物中，抗氧化应激筛选已经产生了长寿的突变体。因此，为了获得一组潜在的人类长寿基因，Kenyon实验室在人类原代细胞系中进行了全基因组siRNA筛选，以获得抗氧化应激能力。基因命中包括已知的C。线虫FOXO调节子，其他长寿蛋白如TOR和NRF 2的调节子，以及新基因。 凯尼恩实验室将从这一组基因中识别出新的人类长寿和健康基因的良好候选者。为了做到这一点，他们将确定哪些基因敲除会触发长寿的其他相关因素，如异源生物素抗性或自噬。此外，他们还将询问哪些敲除会干扰FOXO 3A、TOR或NRF 2的活性。最后，为了将这些基因与长寿联系起来，他们将测试它们的能力， 影响C. elegans及其在百岁老人家庭中的表达改变。 这种新方法将定义新的潜在药物靶点，以延长人类生命的年轻和富有成效的岁月，并延缓癌症、心脏病和/或神经退行性疾病等与年龄相关的疾病。 公共卫生关系：改变特定的基因可以延长健康的寿命，并抵消动物中与年龄有关的疾病，这一奇妙的发现使得寻找人类长寿基因势在必行。这项研究采取了一种新的方法，通过寻找基因，当改变时，从人类培养细胞的特性，从健康，长寿的动物突变体和非常长寿的动物物种培养细胞的特性。这项研究将为延长人类生命的年轻和富有成效的岁月，以及延缓癌症、心脏病和神经退行性疾病等与年龄相关的疾病确定新的切入点。