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EBioMedicine. 2019 Sep;47:446-456. doi: 10.1016/j.ebiom.2019.08.069. Epub 2019 Sep 18.

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

Author information

1
Cellular Senescence and Translation and Pharmacology Programs, Robert and Arlene Kogod Center on Aging, Mayo Clinic, United States of America; Division of Geriatric Medicine and Gerontology, Department of Medicine, Mayo Clinic, United States of America; Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, United States of America.
2
Cellular Senescence and Translation and Pharmacology Programs, Robert and Arlene Kogod Center on Aging, Mayo Clinic, United States of America.
3
Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, United States of America.
4
Cellular Senescence and Translation and Pharmacology Programs, Robert and Arlene Kogod Center on Aging, Mayo Clinic, United States of America; Department of Medicine Clinical Trials Unit, Department of Medicine, Mayo Clinic, United States of America.
5
Cellular Senescence and Translation and Pharmacology Programs, Robert and Arlene Kogod Center on Aging, Mayo Clinic, United States of America; Division of Hematology, Department of Medicine, Mayo Clinic, United States of America.
6
Division of Endocrinology, Department of Medicine, Mayo Clinic, United States of America.
7
Department of Surgery, Mayo Clinic, United States of America.
8
Cellular Senescence and Translation and Pharmacology Programs, Robert and Arlene Kogod Center on Aging, Mayo Clinic, United States of America; Division of Endocrinology, Department of Medicine, Mayo Clinic, United States of America.
9
Cellular Senescence and Translation and Pharmacology Programs, Robert and Arlene Kogod Center on Aging, Mayo Clinic, United States of America; Department of Physiology and Biomedical Engineering, Mayo Clinic, United States of America.
10
Division of Hospital Medicine, Department of Medicine, Mayo Clinic, United States of America.
11
Cellular Senescence and Translation and Pharmacology Programs, Robert and Arlene Kogod Center on Aging, Mayo Clinic, United States of America; Department of Physiology, Mayo Clinic, United States of America; Department of Physical Medicine and Rehabilitation, Mayo Clinic, United States of America.
12
Cellular Senescence and Translation and Pharmacology Programs, Robert and Arlene Kogod Center on Aging, Mayo Clinic, United States of America; Office of Research Regulatory Support, Mayo Clinic, United States of America.
13
Cellular Senescence and Translation and Pharmacology Programs, Robert and Arlene Kogod Center on Aging, Mayo Clinic, United States of America; Division of Geriatric Medicine and Gerontology, Department of Medicine, Mayo Clinic, United States of America; Division of Endocrinology, Department of Medicine, Mayo Clinic, United States of America; Division of Hospital Medicine, Department of Medicine, Mayo Clinic, United States of America; Department of Physiology, Mayo Clinic, United States of America.
14
Cellular Senescence and Translation and Pharmacology Programs, Robert and Arlene Kogod Center on Aging, Mayo Clinic, United States of America. Electronic address: Tchkonia.Tamar@Mayo.edu.
15
Cellular Senescence and Translation and Pharmacology Programs, Robert and Arlene Kogod Center on Aging, Mayo Clinic, United States of America; Division of Geriatric Medicine and Gerontology, Department of Medicine, Mayo Clinic, United States of America; Division of Hospital Medicine, Department of Medicine, Mayo Clinic, United States of America; Division of General Internal Medicine, Department of Medicine, Mayo Clinic, United States of America. Electronic address: Kirkland.James@Mayo.edu.

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

PMID:
31542391
PMCID:
PMC6796530
DOI:
10.1016/j.ebiom.2019.08.069
[Indexed for MEDLINE]
Free PMC Article

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