iProXProteomicsYaohui HeHomo Sapienshttp://www.iprox.org/page/project.html?id=IPX00163490002024001050@usc.edu.cnUniversity of South ChinaiProXCellular senescence is a key driver of kidney aging, leading to functional decline and increased susceptibility to chronic kidney disease. While the senolytic combination of dasatinib and quercetin (D + Q) has shown promise in mitigating age-related pathologies, its long-term effects and underlying multi-level systemic mechanisms in the aging kidney remain poorly defined. Here, we systematically evaluated the long-term effects of D + Q in naturally aged mice using multi-omics approaches. We show that D + Q treatment reduces senescence markers (p16, p21, SA-β-gal), restores the anti-aging protein Klotho, and attenuates renal fibrosis and inflammation. Proteomic profiling reveals that D + Q enhances apoptotic clearance of senescent cells and promotes proliferative and regenerative pathways. Moreover, D + Q reactivates PPARα signaling, improves fatty acid oxidation, and reduces lipid accumulation in aged kidneys. Single-cell transcriptomics further demonstrates that D + Q reverses transcriptional aging signatures across multiple renal cell types and remodels cell-type-specific pathways associated with metabolism, inflammation, and fibrosis. Cell-cell communication analysis reveals that D + Q normalizes the hyperconnected intercellular network in aged kidneys, particularly by modulating inflammation-related signaling. Our findings offer a comprehensive, systems-level understanding of how senolytic therapy restores renal homeostasis, emphasizing its potential as a multifaceted intervention to combat kidney aging.Multi-omics profiling reveals systemic rejuvenation of the aged kidney through senolytic therapy.Chen Shilin S, Zhang Chenglin C, Cang Pengxu P, Guo Weiming W, Xiao Liang L, He Yaohui Y, Su Qiang Q, Ouyang Shuhui S, Zha Jinhui J, Maimaitirexiati Gulikezi G, Chen Yuling Y, Qi Xiaoyan X, He Shiheng S, Zhang Qingping Q, Xu Yao Y, Yang Jing J, Fan Gang GfalseMulti-omics profiling reveals systemic rejuvenation of the aged kidney through senolytic therapyCellular senescence is a key driver of kidney aging, leading to functional decline and increased susceptibility to chronic kidney disease. While the senolytic combination of dasatinib and quercetin (D+Q) has shown promise in mitigating age-related pathologies, its long-term effects and underlying multi-level systemic mechanisms in the aging kidney remain poorly defined. Here, we systematically evaluated the long-term effects of D+Q in naturally aged mice using multi-omics approaches. We show that D+Q treatment reduces senescence markers (p16, p21, SA-β-gal), restores the anti-aging protein Klotho, and attenuates renal fibrosis and inflammation. Proteomic profiling reveals that D+Q enhances apoptotic clearance of senescent cells and promotes proliferative and regenerative pathways. Moreover, D+Q reactivates PPARα signaling, improves fatty acid oxidation, and reduces lipid accumulation in aged kidneys. Single-cell transcriptomics further demonstrates that D+Q reverses transcriptional aging signatures across multiple renal cell types and remodels cell-type-specific pathways associated with metabolism, inflammation, and fibrosis. Cell-cell communication analysis reveals that D+Q normalizes the hyperconnected intercellular network in aged kidneys, particularly by modulating inflammation-related signaling. Our findings offer a comprehensive, systems-level understanding of how senolytic therapy restores renal homeostasis, emphasizing its potential as a multifaceted intervention to combat kidney aging.Tue Mar 24 00:00:00 GMT 2026PXD076057960642386771