Molecular signature of parabiosis

点击翻译按钮获取中文摘要

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.