Using cellular co-biosis and age programmable mice to derive a global interaction map of aging hallmarks

项目总结 生物系统被认为会随着时间的推移而失效，这是基于九个“衰老的标志”，它们不知何故导致了 全球范围内组织功能和健康的下降。基于这一范例、干预以及它们的组合， 正在开发中，以减弱每一个特征，并减缓衰老过程。不幸的是，缺乏 对这些老化特征之间相互依赖的洞察，使其难以普遍发展 有效的缓解战略。我们的实验室和其他实验室提供的证据表明，存储信息的丢失 损害细胞机械和身体结构的功能，导致衰老和与年龄相关的疾病。 我们已经开发了ICE系统(Yang et al.2022，由Cell临时接受)，允许空间 以及对哺乳动物表观遗传衰老的时间控制。我们还发现，部分重新编程 使用重新编程因子Oct4、Sox2和Klf4(OSK)，允许细胞检索年轻的 重置表观基因组、逆转多种衰老标志、恢复DNA甲基化的信息 模式恢复到他们以前的年轻状态(Lu等人，2020；Yang等人，2022，暂时被Cell接受)。 在这项研究中，我们利用我们在正向和反向控制衰老速度的能力来测试 假设细胞信息和细胞机械和物理之间的互连丧失 结构是衰老特征的主要驱动因素，也是衰老本身的可逆原因。要做到这一点，我们将 开发第一套荧光标记记者，以监控标记进展和在 并找到促进其共同逆转的方法。这一新工具将与先进的多用途计算机一起使用 新共生系统的组学方法和异质UM-HET3中可编程年龄的小鼠 遗传背景。 这项研究很重要，因为它将为长期存在的关于 老化标志之间的相互联系，例如是否存在等级制度以及如果一个标志的逆转 确保抹去他人的记忆。总之，这项工作将为现场提供一套新颖的可定制工具，以 跟踪和研究这些特征，并检验许多特征在信息级别相交的假设 因此，当核中的信息被重置到年轻状态时，它们是共同可逆的。

PROJECT SUMMARY Biological systems are presumed to fail over time based on nine “hallmarks of aging,” which somehow cause a global decline in tissue function and health. Based on this paradigm, interventions, and combinations of them, are being developed to attenuate each of the hallmarks and slow the aging process. Unfortunately, a lack of insight into the interdependence among these aging hallmarks has made it difficult to develop universally effective mitigation strategies. Our lab and others have provided evidence that a loss of stored information impairs the function of cellular machinery and physical structures, leading to aging and age-related diseases. We have developed the ICE system (Yang et al. 2022, provisionally accepted by Cell) which allows for spatial and temporal control over epigenetic aging in mammals. We have also discovered that partial reprogramming using the reprogramming factors, Oct4, Sox2, and Klf4 (OSK), allows cells to retrieve a “backup copy” of youthful information that resets the epigenome, reverses multiple hallmarks of aging, and restores DNA methylation patterns to their previous youthful state (Lu et al., 2020; Yang et al., 2022, provisionally accepted by Cell). In this study, we leverage our ability to control the pace of aging in forward and reverse directions to test the hypothesis that a loss of interconnectivity between cellular information and cellular machinery and physical structures is a primary driver of the Hallmarks of Aging and a reversible cause of aging itself. To do this, we will develop the first set of fluorescent hallmark reporters to monitor hallmark progression and interactions during aging and discover ways to promote their co-reversal. This novel tool will be utilized along with advanced multi- omic approaches in novel co-biosis systems and age-programmable mice in the heterogeneous UM-HET3 genetic background. This study is important because it will provide valuable knowledge concerning the long-standing questions about interconnectivity among the aging hallmarks, such as whether hierarchies exist and if the reversal of one hallmark ensures the erasure of others. Together, this work will provide the field with a novel set of customizable tools to track and study these hallmarks and test the hypothesis that many hallmarks intersect at the informational level and are therefore co-reversible when information in the nucleus is reset to a youthful state.