TY - JOUR
T1 - Senolytics decrease senescent cells in humans
T2 - Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease
AU - Hickson, La Tonya J.
AU - Langhi Prata, Larissa G.P.
AU - Bobart, Shane A.
AU - Evans, Tamara K.
AU - Giorgadze, Nino
AU - Hashmi, Shahrukh K.
AU - Herrmann, Sandra M.
AU - Jensen, Michael D.
AU - Jia, Qingyi
AU - Jordan, Kyra L.
AU - Kellogg, Todd A.
AU - Khosla, Sundeep
AU - Koerber, Daniel M.
AU - Lagnado, Anthony B.
AU - Lawson, Donna K.
AU - LeBrasseur, Nathan K.
AU - Lerman, Lilach O.
AU - McDonald, Kathleen M.
AU - McKenzie, Travis J.
AU - Passos, João F.
AU - Pignolo, Robert J.
AU - Pirtskhalava, Tamar
AU - Saadiq, Ishran M.
AU - Schaefer, Kalli K.
AU - Textor, Stephen C.
AU - Victorelli, Stella G.
AU - Volkman, Tammie L.
AU - Xue, Ailing
AU - Wentworth, Mark A.
AU - Wissler Gerdes, Erin O.
AU - Zhu, Yi
AU - Tchkonia, Tamara
AU - Kirkland, James L.
N1 - Publisher Copyright:
© 2019
PY - 2019/9
Y1 - 2019/9
N2 - 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 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.
AB - 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 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.
KW - Cellular senescence
KW - Dasatinib
KW - Diabetic kidney disease
KW - Quercetin
KW - Senescence-associated secretory phenotype
KW - Senolytics
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U2 - 10.1016/j.ebiom.2019.08.069
DO - 10.1016/j.ebiom.2019.08.069
M3 - Article
C2 - 31542391
AN - SCOPUS:85072276259
SN - 2352-3964
VL - 47
SP - 446
EP - 456
JO - EBioMedicine
JF - EBioMedicine
ER -