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

La Tonya J. Hickson, Larissa G.P. Langhi Prata, Shane A. Bobart, Tamara K. Evans, Nino Giorgadze, Shahrukh K. Hashmi, Sandra M. Herrmann, Michael D. Jensen, Qingyi Jia, Kyra L. Jordan, Todd A. Kellogg, Sundeep Khosla, Daniel M. Koerber, Anthony B. Lagnado, Donna K. Lawson, Nathan K. LeBrasseur, Lilach O. Lerman, Kathleen M. McDonald, Travis J. McKenzie, João F. PassosRobert 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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)446-456
Number of pages11
JournalEBioMedicine
Volume47
DOIs
StatePublished - Sep 2019

Fingerprint

Quercetin
Diabetic Nephropathies
Clinical Trials
Macrophages
Tissue
Skin
Galactosidases
Adipose Tissue
Biopsy
Stem cells
Matrix Metalloproteinases
Interleukin-1
Phenotype
Labels
Interleukin-6
Blood
Aging of materials
Dasatinib
Idiopathic Pulmonary Fibrosis
Langerhans Cells

Keywords

  • Cellular senescence
  • Dasatinib
  • Diabetic kidney disease
  • Quercetin
  • Senescence-associated secretory phenotype
  • Senolytics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Senolytics decrease senescent cells in humans : Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. / Hickson, La Tonya J.; Langhi Prata, Larissa G.P.; Bobart, Shane A.; Evans, Tamara K.; Giorgadze, Nino; Hashmi, Shahrukh K.; Herrmann, Sandra M.; Jensen, Michael D.; Jia, Qingyi; Jordan, Kyra L.; Kellogg, Todd A.; Khosla, Sundeep; Koerber, Daniel M.; Lagnado, Anthony B.; Lawson, Donna K.; LeBrasseur, Nathan K.; Lerman, Lilach O.; McDonald, Kathleen M.; McKenzie, Travis J.; Passos, João F.; Pignolo, Robert J.; Pirtskhalava, Tamar; Saadiq, Ishran M.; Schaefer, Kalli K.; Textor, Stephen C.; Victorelli, Stella G.; Volkman, Tammie L.; Xue, Ailing; Wentworth, Mark A.; Wissler Gerdes, Erin O.; Zhu, Yi; Tchkonia, Tamara; Kirkland, James L.

In: EBioMedicine, Vol. 47, 09.2019, p. 446-456.

Research output: Contribution to journalArticle

Hickson, LTJ, 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, Victorelli, SG, Volkman, TL, Xue, A, Wentworth, MA, Wissler Gerdes, EO, Zhu, Y, Tchkonia, T & Kirkland, JL 2019, 'Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease', EBioMedicine, vol. 47, pp. 446-456. https://doi.org/10.1016/j.ebiom.2019.08.069
Hickson, La Tonya J. ; Langhi Prata, Larissa G.P. ; Bobart, Shane A. ; Evans, Tamara K. ; Giorgadze, Nino ; Hashmi, Shahrukh K. ; Herrmann, Sandra M. ; Jensen, Michael D. ; Jia, Qingyi ; Jordan, Kyra L. ; Kellogg, Todd A. ; Khosla, Sundeep ; Koerber, Daniel M. ; Lagnado, Anthony B. ; Lawson, Donna K. ; LeBrasseur, Nathan K. ; Lerman, Lilach O. ; McDonald, Kathleen M. ; McKenzie, Travis J. ; Passos, João F. ; Pignolo, Robert J. ; Pirtskhalava, Tamar ; Saadiq, Ishran M. ; Schaefer, Kalli K. ; Textor, Stephen C. ; Victorelli, Stella G. ; Volkman, Tammie L. ; Xue, Ailing ; Wentworth, Mark A. ; Wissler Gerdes, Erin O. ; Zhu, Yi ; Tchkonia, Tamara ; Kirkland, James L. / Senolytics decrease senescent cells in humans : Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. In: EBioMedicine. 2019 ; Vol. 47. pp. 446-456.
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title = "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 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.",
keywords = "Cellular senescence, Dasatinib, Diabetic kidney disease, Quercetin, Senescence-associated secretory phenotype, Senolytics",
author = "Hickson, {La Tonya J.} and {Langhi Prata}, {Larissa G.P.} and Bobart, {Shane A.} and Evans, {Tamara K.} and Nino Giorgadze and Hashmi, {Shahrukh K.} and Herrmann, {Sandra M.} and Jensen, {Michael D.} and Qingyi Jia and Jordan, {Kyra L.} and Kellogg, {Todd A.} and Sundeep Khosla and Koerber, {Daniel M.} and Lagnado, {Anthony B.} and Lawson, {Donna K.} and LeBrasseur, {Nathan K.} and Lerman, {Lilach O.} and McDonald, {Kathleen M.} and McKenzie, {Travis J.} and Passos, {Jo{\~a}o F.} and Pignolo, {Robert J.} and Tamar Pirtskhalava and Saadiq, {Ishran M.} and Schaefer, {Kalli K.} and Textor, {Stephen C.} and Victorelli, {Stella G.} and Volkman, {Tammie L.} and Ailing Xue and Wentworth, {Mark A.} and {Wissler Gerdes}, {Erin O.} and Yi Zhu and Tamara Tchkonia and Kirkland, {James L.}",
year = "2019",
month = "9",
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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.

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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