Senolytic Drugs, Dasatinib and Quercetin, Attenuate Adipose Tissue T Lymphocyte Infiltration and Improve Metabolic Function in Old Mice

Abstract

Age‐related metabolic dysfunction is accompanied by accumulation of senescent cells and the senescence‐associated secretory phenotype (SASP) leading to chronic sterile inflammation. Recent evidence suggests that using a genetic approach to clear senescent cells improves metabolic function in old mice. However, the underlying mechanisms and if/how these findings can be translated into clinical practice are largely unknown. Here, we evaluated the impact of treatment with the FDA‐approved drugs, dasatinib and quercetin (D&Q), on tissue senescence burden, T lymphocyte infiltration and systemic metabolic function in 22‐24 month old C57Bl/6 mice. Administration of D&Q resulted in ~50% reduction in expression of the senescence marker p16 in perigonadal white adipose tissue (pgWAT) (p=0.004) and liver (p=0.003) (Fig 1A), but not skeletal muscle (p=0.76). D&Q treatment also resulted in 1 to 4‐fold reduction in expression of pro‐inflammatory SASP genes (i.e., mcp1, cxcl2, il‐6 and il‐1β) in pgWAT (all p≤0.04; Fig 1B), but not in liver and skeletal muscle (all p≥0.19), suggesting an adipose specific effect of D&Q. Using flow cytometry, we found that the reduced expression of p16 and SASP genes was associated with 30‐50% lower infiltration of total (CD3+), cytotoxic (CD8+) and helper (CD4+) T cells in pgWAT (all p≤0.04; Fig 1C). Treatment with D&Q ameliorated glucose tolerance (2 g/kg, ip) as demonstrated by a lower time response curve (group: p=0.007, interaction: p=0.03, Fig 1D) and reduced area under the curve (p=0.01, Fig 1E). To explore the underlying mechanisms, we assessed glucose‐stimulated (2 g/kg, ip) insulin secretion and insulin tolerance (1 U/kg, ip) and found no differences between groups (both p≥0.19). To assess the impact of D&Q on metabolic function in the liver, we performed a pyruvate tolerance (2 g/kg, ip) test and found that this treatment resulted in improved pyruvate tolerance (group: p=0.08, interaction: p=0.04, Fig 2A) and thus attenuated hepatic gluconeogenesis. Biochemical analysis revealed that phosphorylation of a gluconeogenic transcription factor, cAMP response element binding protein, and transcript level expression of gluconeogenic genes (pck1, pck2, fbp2 and g6pc) were lower in D&Q treated mice compared to vehicle treated mice (all p≤0.04; Fig 2B‐D), further supporting our findings of diminished hepatic gluconeogenesis. D&Q treatment also reduced plasma triglycerides (113 ± 5 vs 94 ± 5 mg/dL, p=0.02) and improved adipose tissue sensitivity to insulin as indicated by lower insulin‐stimulated ((1 U/kg, ip) plasma non‐esterified free fatty acids (fasted: 0.63 ± 0.02 vs 0.62 ± 0.06 mmol/L, p=0.87; 15 min: 0.54 ± 0.05 vs 0.33 ± 0.02 mmol/L, p=0.006). Taken together, these results suggest that D&Q improve glucose tolerance and lipid metabolism, associated with an attenuation of adipose inflammation (i.e., reduced SASP gene expression and T cell infiltration) and reduced hepatic gluconeogenesis in old mice.

Enhanced Autophagic Flux, Suppressed Apoptosis and Reduced Macrophage Infiltration by Dasatinib in Kidneys of Obese Mice

“…Dasatinib and Quercetin, which constitute senolytic therapy, could suppress renal senescence and attenuate renal fibrosis in both unilateral renal ischemia/reperfusion and multiple-cisplatin treatment models; thus, they might be promising for treating chronic kidney disease after acute kidney injury [ 53 ]. Furthermore, senolytic therapy could modulate glucose tolerance and lipid metabolism, with the suppression of adipose tissue inflammation, T lymphocyte cellular infiltration, reduction in senescent cells and attenuation of hepatic gluconeogenesis in old mice [ 54 ]. Moreover, Src inhibition by Dasatinib was found to increase the accumulation of apical membrane Aquaporin 2 (AQP2) in the principal cells of the collecting duct, thus regulating water reabsorption, and this might be a different mechanism underlying the therapeutic effect of Dasatinib in ORC [ 55 ].…”