EBioMedicine 47 (2019) 446–456
Author: LaTonya J. Hickson, Larissa G.P. Langhi Prata, Shane A. Bobart, Tamara K. Evans, Nino Giorgadze, Shahrukh K. Hashmi, SandraM. Herrmann, MichaelD. Jensen, Qingyi Jia, Kyra L. Jordan, ToddA. Kellogg, Sundeep Khosla, Daniel M. Koerber, Anthony B. Lagnado, Donna K. Lawsoni, 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, James L. Kirkland
Date: 11.22.2019
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 senolytictreatment. 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.
Reference:
- Farr JN, Fraser DG, Wang H, Jaehn K, Ogrodnik MB, Weivoda MM, et al. Identification of senescent cells in the bone microenvironment. J Bone Miner Res 2016;31:1920–9.
- Zhu Y, Armstrong JL, Tchkonia T, Kirkland JL. Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr Opin Clin Nutr Metab Care 2014;17:324–328.
- Tchkonia T, Morbeck DE, von Zglinicki T, van Deursen J, Lustgarten J, Scrable H, et al.Fat tissue, aging, and cellular senescence. Aging Cell 2010;9:667–84.
- Justice, J.N., Nambiar, A.M., Tchkonia, T., LeBrasseur, N.K., Pascual, R., Hashmi, S.K. et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine. 2019; 40: 554–563.
- Wang, A.S. and Dreesen, O. Biomarkers of cellular senescence and skin aging. Front Genet. 2018; 9: 247.
指導教授：徐堯煇、王敏盈 教授
報告序號：20191121-1
組員：生技碩二 陳品宏
生技碩一 廖俞蕙
