Multi-omics Decoding Renal Aging: Unveiling Overexpressed Galectin-9 and Increased Immune Cell Subset Ly6c2+Ccr2+Macrophage as Critical Drivers of Kidney Aging (PRJCA019085)

Renal aging is an important cause of increased susceptibility to kidney disease and has become a considerable burden on global health. Consequently, mitigating or preventing renal aging can make a momentous contribution to human well-being. The objective of this study was to explore the molecular characteristics of renal aging across various omics levels. We identified potential metabolic molecular biomarkers of renal aging, and revealed molecular characteristics of renal aging at metabolic, protein, and transcriptional levels through renal metabolomics, plasma metabolomics, renal proteomics, and renal bulk transcriptomics of young and old C57BL/6J mice. In addition, the combined single-cell transcriptomic analysis found that macrophages with high expression of Ly6c2 and Ccr2 (Ly6c2+Ccr2+Mac) accounted for an increased proportion of immune cells in aging kidneys, and a variety of disease-related genes were mainly expressed in Ly6c2+Ccr2+Mac. Compared with the immune cells of the young kidney, the communication frequency of several signalings related to promoting aging was increased in the immune cells of the aging kidney. The increased communication frequency in these aging-related pathways was primarily observed within the immune cell subset Ly6c2+Ccr2+Mac. Moreover, we made a significant discovery and validated that the overexpression of Lgals9 promoted kidney aging, and notably, Lgals9 was predominantly expressed in the immune cell subset Ly6c2+Ccr2+Mac. These results indicate that Ly6c2+Ccr+Mac and Lgals9 are key drivers of renal aging, which lays the foundation for the development of drugs to intervene in renal aging at the cellular and molecular levels.