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

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/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. FINDINGS:D?+?Q reduced adipose tissue senescent cell burden within 11?days, with decreases in p16INK4A-and p21CIP1-expressing cells, cells with senescence-associated ?-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-1?, 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.

SUBMITTER: Hickson LJ

PROVIDER: S-EPMC6796530 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Hickson LaTonya J LJ Langhi Prata Larissa G P LGP Bobart Shane A SA Evans Tamara K TK Giorgadze Nino N Hashmi Shahrukh K SK Herrmann Sandra M SM Jensen Michael D MD Jia Qingyi Q Jordan Kyra L KL Kellogg Todd A TA Khosla Sundeep S Koerber Daniel M DM Lagnado Anthony B AB Lawson Donna K DK LeBrasseur Nathan K NK Lerman Lilach O LO McDonald Kathleen M KM McKenzie Travis J TJ Passos João F JF Pignolo Robert J RJ Pirtskhalava Tamar T Saadiq Ishran M IM Schaefer Kalli K KK Textor Stephen C SC Victorelli Stella G SG Volkman Tammie L TL Xue Ailing A Wentworth Mark A MA Wissler Gerdes Erin O EO Zhu Yi Y Tchkonia Tamara T Kirkland James L JL

EBioMedicine 20190918

<h4>Background</h4>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 ...[more]

PMID: 31542391

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Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is an age-related, chronic, irreversible fibrotic lung disease. IPF is associated with increased senescent cells burden, which may be alleviated with administration of senescent cell targeting drugs termed 'senolytics'. We previously conducted an open-label single-arm pilot study of the senolytic combination of dasatinib and quercetin (D + Q) in patients with IPF but lack of control group limited interpretation and next-stage trial planning. The primary objective of this confirmatory randomized placebo-controlled pilot trial (RCT; NCT02874989) was to report adverse events with D + Q and inform study feasibility for future efficacy trials.MethodsTwelve participants with IPF aged >50 years were blinded and randomized at a 1:1 ratio to either receive three weeks of D + Q (D: 100 mg/d and Q: 1250 mg/d, three consecutive days per week) or matching placebo.FindingsAll participants completed the scheduled drug dosing regimen (108/108 doses) and planned assessments (60/60). While the placebo arm reported fewer overall non-serious AEs (65 vs 22), there were no serious adverse events related to D + Q. Most AEs in the D + Q arm are common in IPF patients or anticipated side effects of D. Sleep disturbances and anxiety were disproportionately represented in the D + Q arm (4/6 vs 0/6). Frailty, pulmonary, or physical function were explored before and after intermittent D + Q; though under-powered to evaluate change, these measures do not appear to differ meaningfully between groups.InterpretationIntermittently-dosed D + Q in patients with IPF is feasible and generally well-tolerated. Further prospective studies, such as a larger RCT, are needed to confirm the safety and efficacy of D + Q in patients with IPF.FundingThis work was supported by National Institutes of Health grants R33AG61456 (JLK, TT), Robert and Arlene Kogod (JLK, TT), the Connor Fund (JLK, TT), Robert J. and Theresa W. Ryan (JLK, TT), and the Noaber Foundation (JLK, TT) San Antonio Claude D. Pepper Older Americans Independence Center's (OAIC)Pilot/Exploratory Studies Core (PESC) Grant (AMN, NM); NIHK01 AG059837 (JNJ), P30 AG021332 (SBK, JNJ); NIHR37 AG013925 (JLK), the Connor Group (JLK), Glenn/AFAR BIG Award (JLK), Robert J. and Theresa W. Ryan (JLK), and the Noaber and Ted Nash Long Life Foundations (JLK).

Project description:The senolytics dasatinib and quercetin (DQ) alleviate age‑related disorders. However, limited information is available regarding the effects of DQ on diabetic kidney disease (DKD). The present study aimed to explore the effects of DQ on DKD and its potential molecular mechanism(s). Dasatinib (5 mg/kg) and quercetin (50 mg/kg) were administered to diabetic db/db mice by gavage for 20 weeks. Body weight, urine albumin‑creatinine ratio (ACR), serum creatinine (Scr), and blood urea nitrogen (BUN) were recorded at the indicated time periods. Periodic acid‑Schiff and Masson's staining were performed to assess the histopathological changes of kidney tissues. Immunohistochemical analysis, immunofluorescence and western blotting were performed to evaluate the expression levels of extracellular matrix (ECM) proteins, autophagic and podocyte differentiation‑related proteins. In addition, mouse podocytes were administered with high‑glucose, DQ and 3‑methyladenine (3‑MA), and the expression levels of autophagic and podocyte differentiation‑related proteins were measured. Moreover, following overexpression of the Notch intracellular domain (NICD), the expression levels of NICD, autophagic and podocyte differentiation‑related proteins were further assessed. DQ significantly reduced the body weight, blood glucose, ACR, Scr and BUN levels and improved the histopathological changes induced in diabetic db/db mice. In addition, DQ caused a significant downregulation of the expression levels of the ECM proteins, improved autophagy and induced an upregulation of the expression levels of podocyte differentiation‑related proteins. Administration of 3‑MA to mice significantly reduced podocyte differentiation, and overexpression of NICD could reverse the effects of DQ on autophagy and podocyte differentiation in vitro. The present study suggests that DQ protects against DKD by activation of autophagy to alleviate podocyte dedifferentiation via the Notch pathway.

Dataset Information

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

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

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