Health + Life Science Alliance Heidelberg Mannheim

Aging is major driver of cardiovascular disease. In this project, we found that cardiac dysfunction develops in the late lifespan of mice (typically within the second year of age) and includes prominent myocardial fibrosis, inflammation, and degeneration of vascular endothelial cells. Genetic deletion of a fibrogenic transcription factor in mice prevented all these hallmarks of disease and maintained cardiac function until two years of age, which is the typical murine end of life. Specific single-cell RNA sequencing of cardiac non-myocyte cells revealed at least three different, endothelial cell-driven mechanisms of cardiac aging that might be therapeutically useful: maturation of fibroblasts, and activation of regulatory immune cells by paracrine signaling, as well as endothelial senescence. To test a therapeutic approach, we modified endothelial cells in aged, cardiac-diseased mice and ameliorated their condition.