• LaTonya J Hickson, Larissa G P Langhi Prata, Shane A Bobart, Tamara K Evans, Nino Giorgadze, Shahrukh K Hashmi, Sandra M Herrmann, Michael D Jensen, Qingyi Jia, Kyra L Jordan, Todd A Kellogg, Sundeep Khosla, Daniel M Koerber, Anthony B Lagnado, Donna K Lawson, Nathan K LeBrasseur, Lilach O Lerman, Kathleen M McDonald, Travis J McKenzie, João F Passos, Robert J Pignolo, Tamar Pirtskhalava, Ishran M Saadiq, Kalli K Schaefer, Stephen C Textor, Stella G Victorelli, Tammie L Volkman, Ailing Xue, Mark A Wentworth, Erin O Wissler Gerdes, Yi Zhu, Tamara Tchkonia, and James L Kirkland.
• Cellular Senescence and Translation and Pharmacology Programs, Robert and Arlene Kogod Center on Aging, Mayo Clinic, United States of America; Division of Geriatric Medicine and Gerontology, Department of Medicine, Mayo Clinic, United States of America; Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, United States of America.
• EBioMedicine. 2019 Sep 1; 47: 446-456.

BackgroundSenescent 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.MethodsIn 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; 2 female; BMI:33·9 ± 2·3 kg/m2; eGFR:27·0 ± 2·1 mL/min/1·73m2). 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.FindingsD + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16INK4A-and p21CIP1-expressing cells, cells with senescence-associated β-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 p16INK4A+ and p21CIP1+ cells were reduced, as were circulating SASP factors, including IL-1α, 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. FUND: NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.Copyright © 2019. Published by Elsevier B.V.

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