Senolytics Improve Diabetes Measures in Type 2 Diabetic Nonhuman Primates: A Pilot Study

Senescent cells accumulate in adipose tissue (AT) with obesity, causing local inflammation and dysfunction. Senescent cells in aging nonhuman primate (NHP) AT correlated with metabolic disease measures in our previous work. In this pilot study, we evaluated the senolytic combination dasatinib plus quercetin (D+Q) on AT senescent cell burden and systemic metabolic health in obese NHPs with naturally occurring type II diabetes (T2D; n=3). Selected NHPs remained stable on insulin therapy for six months prior to the study. NHPs were given a single oral dose of D (5mg/kg) plus Q (50mg/kg). Blood samples were collected 1 week prior to, and 4 and 8 weeks post-treatment. Abdominal subcutaneous (SQ) AT biopsies were taken before and 1 week after dosing. Senescence-associated beta galactosidase (SA-β-gal) staining showed 24% reductions in AT senescent cell burden. Two animals had large reductions in the senescence biomarker plasminogen activator inhibitor 1 (mean=55%). Dramatic improvements in A1c, fasting glucose (FBG), cholesterol (TPC) and triglycerides (TG) were reported in all subjects, in the absence of weight loss. A1c decreased by 1-2% and FBG by > 100mg/dL (Cohen’s d = 3.81 and 2.78). Post-prandial glucoses were unchanged. Similarly, TPC and TG reduced by >25mg/dL and > 130mg/dL (Cohen’s d = 0.73 and 1.55). Improvements in fasting and overall glycemic measures, and lipid profiles suggest effects on hepatic metabolism. Reductions in creatinine were also seen post-treatment without changes in urea, which may indicate reduced muscle catabolism. Our results show a single D+Q treatment has potent and long-lasting effects for improved metabolism in T2D. Disclosure A. D. Ruggiero: None. M. Block: None. M. Davis: None. R. Vemuri: None. M. E. Orr: None. K. Kavanagh: None. Funding National Heart, Lung, and Blood Institute (R01HL142930)