Abstract
Epigenetic aging is a hallmark of chronic diseases, arising from sustained injuries and unresolved repairs. To investigate cell-type-specific epigenetic alterations, we built a cross-species single-cell multi-omics atlas of DNA methylomes, chromatin accessibilities, and transcriptomes on healthy, injured (human) and aging (mouse) kidneys. We identified accelerated epigenetic aging dominated by tubular epithelia in diseased kidneys. The pathological state mirrors transcriptional trajectories observed in normal aging, driven by the preferential dysregulation of lineage-specific genes lacking CpG islands. Spatially, these epigenetic changes mapped to pathological niches of failed repair. Co-profiling of single-cell DNA methylation and 3D genome architecture revealed that epithelial repair states in disease undergo significant higher-order genome reorganizations, activating genes associated with renal decline. Our findings demonstrate that epithelial aging is driven by a collapse of 3D chromatin structure and local methylome integrity, which silences cell identity and promotes a non-resolving repair state.