{"id":"doi:10.1016/j.ebiom.2019.08.069","kind":"article","title":"Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease","authors":["Hickson LJ","Langhi Prata LGP","Bobart SA","Evans TK","Giorgadze N","Hashmi SK","Herrmann SM","Jensen MD","Jia Q","Jordan KL","Kellogg TA","Khosla S","Koerber DM","Lagnado AB","Lawson DK","LeBrasseur NK","Lerman LO","McDonald KM","McKenzie TJ","Passos JF","Pignolo RJ","Pirtskhalava T","Saadiq IM","Schaefer KK","Textor SC"],"author_count":33,"year":2019,"published":"2019-09-18","venue":"EBioMedicine","cited_by":1119,"doi":"10.1016/j.ebiom.2019.08.069","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1016/j.ebiom.2019.08.069","archive_url":"https://space-kitty.com/papers/doi:10.1016/j.ebiom.2019.08.069","updated":null,"pmid":"31542391","pmcid":"PMC6796530","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC6796530/pdf","abstract":"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; 2 female; 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 -and p21 CIP1 -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 p16 INK4A+ and p21 CIP1+ 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.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease\" by Hickson LJ, Langhi Prata LGP, Bobart SA et al., https://doi.org/10.1016/j.ebiom.2019.08.069, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"aging-longevity","name":"Biology of Aging & Longevity","domain_slug":"medicine"}],"cited_in_dossiers":[]}