Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease

Background: Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D+Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D+Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans. Methods: In an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease (N = 9; 68.7 +/- 3.1 years old; 2female; BMI: 33.9 +/- 2.3 kg/m(2); eGFR: 27.0 +/- 2.1 mL/min/1.73m(2)). Adipose tissue, skin biopsies, and blood were collected before and 11 days after completing senolytic treatment. Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors were assayed. Findings: D+ Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16(INK4A)-andp21(CIP1)-expressing cells, cells with senescence-associated beta-galactosidase activity, and adipocyte progenitors with limited replicative potential. Adipose tissue macrophages, which are attracted, anchored, and activated by senescent cells, and crown-like structures were decreased. Skin epidermal p16(INK4A+) and p21(CIP1+) cells were reduced, as were circulating SASP factors, including IL-1 alpha, IL-6, and MMPs-9 and - 12. Interpretation: "Hit-and-run" treatment with senolytics, which in the case of D+Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans. (C) 2019 Published by Elsevier B.V.