Decoding Aging in the Heart via Single Cell Dual Omics of Non-Cardiomyocytes

To understand heart aging at the single-cell level, we employed single-cell dual omics (scRNA and scATAC) in profiling non-myocytes (non-CMs) from young, middle-aged, and elderly mice. Non-CMs, vital in heart development, physiology, and pathology, are understudied compared to cardiomyocytes. Our analysis revealed aging response heterogeneity and its dynamics over time among non-CM cell types. Immune cells, notably macrophages and neutrophils, showed significant aging alterations, while endothelial cells displayed moderate changes. We identified distinct aging signatures within the cell type, including differential gene expression, transcription factor activity, and motif variation. Sub-cluster analysis revealed intra-cell type heterogeneity, characterized by diverse aging patterns. The senescence-associated secretory phenotype (SASP) emerged as a key aging-related phenotype. Moreover, aging significantly influenced cell-cell communication, especially impacting a fibroblast sub-cluster with high expression of ERBB4. This study elucidates the complex cellular and molecular landscape of cardiac aging in non-CMs. It highlights their importance in cardiac aging and offers guidance for potential therapeutic avenues to treat aging-related heart diseases. The primary focus is on using single-cell dual omics data to identify aging-related changes, including shifts in cell type proportions, enrichment of aging-related gene sets, cell-specific regulatory networks, and cell-cell communication dynamics.