Abstract
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.FundNIH and Foundations.ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.
Highlights
Research in contextEvidence before this studySenescent cells accumulate in tissues with ageing and at etiological sites in multiple chronic diseases, including adipose tissue in diabetes
To exclude the possibility that senescenceassociated β-galactosidase (SAβgal)+ cells could have been induced in the second biopsy due to trauma from the first, we assayed adipose tissue biopsies obtained 15 days apart from women with obesity who were not treated with senolytics
Consistent with the decreases in senescent cell burden and coupled decreases in adipose tissue macrophages from humans with diabetes and chronic kidney disease (CKD) reported here, we found that D + Q significantly decreases crown-like structures” (CLS) in abdominal subcutaneous adipose tissue (p = 0·001)
Summary
Research in contextEvidence before this studySenescent cells accumulate in tissues with ageing and at etiological sites in multiple chronic diseases, including adipose tissue in diabetes. In the first clinical trial of senolytics, D + Q alleviated physical dysfunction in patients with idiopathic pulmonary fibrosis (IPF), a progressive, fatal, cellular senescence-associated disease. In another clinical trial, prolonged D administration to patients with systemic sclerosis appeared to reduce the SASP and other senescence markers in skin biopsies. Senescent cells, which can release factors that cause inflammation and dysfunction, the senescenceassociated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. 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. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents
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