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

使用细胞共生和年龄可编程小鼠来得出衰老标志的全局相互作用图

• 批准号: 10721454
• 负责人: DAVID A. SINCLAIR
• 金额: $ 45.36万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721454
• 关键词: 3-Dimensional; ATAC-seq; Acceleration; Affect; Age; Aging; Appearance; Architecture; Attenuated; Biological; Biology; Categories; Cell Nucleus; Cell physiology; Cells; Complex; Computer software; Cytoplasm; DNA; DNA Methylation; DNA methylation profiling; Data; Disease; Ensure; Epigenetic Process; Feedback; Female; Genetic; Genetic Variation; Genome; Genome Mappings; Genomic Segment; Health; Human; Hybrids; Image; Impairment; Incidence; Individual; Instruction; Intervention; Knowledge; Machine Learning; Mammals; Maps; Measures; Mitochondria; Monitor; Mus; Nuclear; Organ; Physiological; Process; RNA; Reporter; Reporting; Structure; System; Technology; Testing; Time; Tissue Harvesting; Tissues; Work; age related; aged; attenuation; biological systems; cell type; demethylation; epigenome; epigenomics; in vivo; indexing; inducible gene expression; innovation; insight; live cell imaging; male; methylation pattern; multiple omics; novel; pathological aging; programs; sensor technology; siRNA delivery; single-cell RNA sequencing; software development; time use; tool; ultra high resolution

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.

项目摘要 生物系统被认为会随着时间的推移而失败，这是基于九个“衰老的标志”，这以某种方式导致了一个 组织功能和健康的全球性下降。基于这种模式，干预措施，以及它们的组合， 正在开发以减弱每一个特征并减缓衰老过程。不幸的是，缺乏 对这些衰老特征之间相互依赖性的深入了解使得很难普遍地发展 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， 损害细胞机制和身体结构的功能，导致衰老和与年龄有关的疾病。 我们已经开发了ICE系统（Yang et al. 2022，暂时被Cell接受），该系统允许空间 和哺乳动物表观遗传衰老的时间控制。我们还发现部分重编程 使用重编程因子Oct 4、Sox 2和Klf 4（OSK），可以让细胞重新获得年轻细胞的“备份拷贝”。 重置表观基因组的信息，逆转衰老的多个标志，并恢复DNA甲基化 模式到他们以前的年轻状态（Lu等人，2020年; Yang等人，2022年，由Cell暂时接受）。 在这项研究中，我们利用我们在正向和反向方向上控制衰老速度的能力来测试 假设细胞信息和细胞机械之间的相互连接的丢失和物理 结构是老化标志的主要驱动力，也是老化本身的可逆原因。为此，我们将 开发第一套荧光标记报告，以监测标记进展和相互作用， 并发现促进其共同逆转的方法。这种新的工具将被利用沿着与先进的多- 在异质UM-HET 3中的新型共生系统和年龄可编程小鼠中的组学方法 遗传背景 这项研究很重要，因为它将提供有关长期存在的问题的宝贵知识， 老化标志之间的相互联系，例如是否存在等级制度，以及是否有一个标志的逆转 确保删除其他人。总之，这项工作将为该领域提供一套新颖的可定制工具， 跟踪和研究这些标志，并检验许多标志在信息水平上交叉的假设 因此当细胞核中的信息被重置到年轻状态时是共可逆的。