Molecular signature of parabiosis

联体共生的分子特征

• 批准号: 10609087
• 负责人: TONY WYSS-CORAY
• 金额: $ 47.22万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609087
• 关键词: Adipose tissue; Affect; Age; Aging; Animal Model; Atlases; Biochemical; Biochemical Pathway; Biological Aging; Blood; Brain; Cardiovascular system; Cause of Death; Cells; Cessation of life; Chronic Disease; Circulation; Cognition; Data; Data Set; Dementia; Diabetes Mellitus; Disease; Disparate; Endothelial Cells; Exhibits; Exposure to; Future; Gene Expression; Gene Expression Profile; Generations; Genetic Transcription; Goals; Health; Heart Diseases; Hepatocyte; Human; Individual; Inflammation; Injections; Liver; Longevity; Malignant Neoplasms; Mediating; Mediator; Mesentery; Methodology; Methods; Modeling; Molecular; Molecular Profiling; Mus; Ontology; Operative Surgical Procedures; Organ; Organism; Parabiosis; Pathway interactions; Pattern; Phenotype; Plasma; Process; Proteins; Quality of life; Rejuvenation; Research; Resistance; Risk Factors; Sampling; Scientist; System; Testing; Therapeutic; Tissues; Vascular Endothelial Cell; Wild Type Mouse; age effect; age related; aged; aging gene; body system; bone repair; cell type; experience; functional improvement; healthspan; human old age (65+); improved; mitochondrial dysfunction; muscle strength; new therapeutic target; normal aging; novel; novel therapeutics; prevent; programs; proteostasis; rational design; response; single-cell RNA sequencing; small molecule; targeted treatment; temporal measurement; trafficking; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Aging is the single greatest cause of disease and death worldwide, and rejuvenating the body by targeting biological aging processes therefore holds potential to simultaneously prevent multiple chronic diseases like cancer, heart disease, dementia, and diabetes. While decades of research has unveiled common hallmarks of aging, like mitochondrial dysfunction, inflammation, and loss of proteostasis, therapies targeting these hallmarks have elicited only modest rejuvenation in animal models. This may be in part because most aging studies have focused on only one or a few organs or cell types, with little to no temporal resolution, limiting our ability to interpret how and when aging impacts these interconnected systems. Recently, however, we have attempted such a systematic characterization of aging. Using bulk RNA-sequencing (RNA-seq) and single-cell RNA- sequencing (scRNA-seq) on dozens of mouse organs and cell types across the lifespan (termed Tabula Muris Senis), we discovered global and specific aging signatures throughout the body. But it remains unknown how, or if, rejuvenation paradigms affect these global aging pathways, or rather instigate nascent biochemical programs. The rational design of new therapeutics is therefore challenging. One method of rejuvenation which has garnered beneficial effects across organ systems is heterochronic parabiosis, in which a young and old mouse share a common circulation. Phenotypes like cognition, muscle strength, and bone repair have all shown functional improvement through exposure to young blood. Parabiosis research has largely focused on age-related changes to circulating proteins, and several have been determined to mediate at least some of the observed effects. However, such individual factors have yet to achieve robust rejuvenation throughout the body, likely in part due to an incomplete understanding of the effects of parabiosis on disparate organs and cells. Using our newly created Tabula Muris Senis data to represent normal aging, we investigated scRNA-seq changes in 3 tissues following parabiosis: gonadal and mesenteric adipose tissues, which undergo age-related gene expression changes prior to other organs, and liver, as hepatocytes were one of the first cell types observed to benefit from exposure to a young circulatory system. Interestingly, individual cell types vary greatly in their response to parabiosis, with vascular endothelial cells from all 3 tissues showing prominent transcriptomic changes consistent with normal aging genes. It is our hope that by expanding this analysis to scRNA-seq of 9 tissues, and to bulk RNA-seq of 21 tissues, we can discover signatures that will serve as the basis for identifying small molecules capable of robust rejuvenation and healthspan extension. As surgically intensive parabiosis is confounded by cell trafficking and simultaneous exposure to young and aged circulating factors, we further propose to compare parabiosis signatures to those derived from young plasma transfer, thereby uncovering aspects of rejuvenation specifically sensitive to alterations in plasma factors. Similar to our earlier datasets, all data will be made publically available.

项目总结 衰老是全世界疾病和死亡的唯一最大原因，并通过靶向使身体恢复活力 因此，生物衰老过程有可能同时预防多种慢性疾病，如 癌症、心脏病、痴呆症和糖尿病。虽然几十年的研究揭示了 衰老，如线粒体功能障碍、炎症和蛋白平衡丧失，针对这些特征的治疗 只在动物模型中引发了适度的恢复活力。这可能在一定程度上是因为大多数衰老研究 只关注一个或几个器官或细胞类型，几乎没有时间分辨率，限制了我们的能力 解释老化如何以及何时影响这些相互连接的系统。然而，最近我们试图 这样系统地刻画了衰老。使用整体RNA测序(RNA-SEQ)和单细胞RNA- 对数十个小鼠器官和细胞类型的测序(称为Tabula Muris) (Senis)，我们发现了遍及全身的全球和特定的衰老特征。但目前还不清楚是如何做到的， 或者，如果复兴范式影响这些全球衰老途径，或者更确切地说，煽动新生的生物化学 程序。因此，新疗法的合理设计是具有挑战性的。 跨器官系统获得有益效果的一种返老还童的方法是异步法 异种共生：一只幼鼠和一只老年鼠共用一个循环。表型，如认知，肌肉 通过接触年轻的血液，力量和骨骼修复都显示出功能的改善。异型共生 研究主要集中在与年龄相关的循环蛋白质的变化上，已经确定了几个 以调解至少部分观察到的影响。然而，这些个人因素还没有达到强劲的水平。 全身返老还童，部分原因可能是对异种共生的影响不完全了解 在不同的器官和细胞上。使用我们新创建的Tabula Muris Senis数据来代表正常衰老，我们 研究了异种繁殖后3种组织中scRNA-seq的变化：性腺和肠系膜脂肪组织， 它们的年龄相关基因表达变化先于其他器官，肝脏，因为肝细胞是一个 在观察到的第一批受益于年轻循环系统的细胞类型中。有趣的是，个人 细胞类型对异种共生的反应差异很大，所有三种组织的血管内皮细胞都表现出 显著的转录转录变化与正常衰老基因一致。 我们希望通过将这种分析扩展到9种组织的scRNA-seq和21种组织的散装rna-seq 组织，我们可以发现将作为识别能够强大的小分子的基础的特征 返老还童，延年益寿。由于手术密集型异种生物被细胞贩运和 同时接触年轻和老年循环因子，我们进一步建议比较异种共生 那些来自年轻血浆转移的签名，从而揭示了年轻化的具体方面 对血浆因子的变化敏感。与我们之前的数据集类似，所有数据都将公开可用。