Human Gene Knockdowns that May Extend Lifespan

描述（由申请人提供）：FOXO 转录因子可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 FOXO3A DNA 变体与人类的超长寿命联系起来。因此，寻找可能调节 FOXO 依赖性或其他长寿途径的人类基因似乎是时候了。 FOXO 蛋白可以通过多种方式激活以延长动物寿命。例如，线虫 FOXO 可以响应胰岛素/IGF-1 信号减弱、血清素信号传导改变、AMP 激酶活性升高、热休克因子活性升高、lin-4 microRNA 活性升高、Jun 激酶活性升高和其他输入而促进寿命。因此，可能有许多基因扰动可以延长人类的健康寿命。其中一些扰动可能比其他扰动更安全、更有效。 因为不可能对长寿的人类进行基因筛查，所以我们正在人类细胞中进行基因筛查。我们的实验策略基于这样的观察：迄今为止测试的所有 FOXO 依赖性延长寿命途径（以及许多其他延长寿命途径）都增加了对氧化应激的抵抗力。尽管氧化应激抵抗力在延长寿命中的作用尚不清楚，但相关性是 足够严格，以至于在许多模型生物体中，氧化应激抗性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实验室对人类原代细胞系的氧化应激抗性进行了全基因组siRNA筛选。命中的基因包括已知的线虫 FOXO 调节因子、TOR 和 NRF2 等其他长寿蛋白的调节因子，以及新基因。 凯尼恩实验室将从这组基因中找出新的人类长寿和健康基因的良好候选者。为此，他们将确定哪些击倒会引发其他与长寿相关的因素，例如外源抗性或自噬。此外，他们还会询问哪些敲低会扰乱 FOXO3A、TOR 或 NRF2 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 影响线虫的寿命及其在百岁家庭中表达的改变。 这种新方法将确定新的潜在药物靶点，以延长人类生命的年轻和富有生产力的岁月，并延缓与年龄相关的疾病，如癌症、心脏病和/或神经退行性疾病。

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.