학술논문
Identification of HSP90 inhibitors as a novel class of senolytics.
Document Type
Academic Journal
Author
Fuhrmann-Stroissnigg H; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, 33458, FL, USA.; Ling YY; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, 33458, FL, USA.; Zhao J; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, 33458, FL, USA.; McGowan SJ; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, 33458, FL, USA.; Zhu Y; University of Pittsburgh School of Medicine, Pittsburgh, 15261, PA, USA.; Brooks RW; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, 33458, FL, USA.; Grassi D; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, 33458, FL, USA.; Gregg SQ; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, 55905, MN, USA.; Stripay JL; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, 55905, MN, USA.; Dorronsoro A; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, 33458, FL, USA.; Corbo L; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, 33458, FL, USA.; Tang P; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, 33458, FL, USA.; Bukata C; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, 33458, FL, USA.; Ring N; International Centre for Genetic Engineering and Biotechnology, Trieste, 34100, Italy.; Giacca M; International Centre for Genetic Engineering and Biotechnology, Trieste, 34100, Italy.; Li X; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, 33458, FL, USA.; Tchkonia T; University of Pittsburgh School of Medicine, Pittsburgh, 15261, PA, USA.; Kirkland JL; University of Pittsburgh School of Medicine, Pittsburgh, 15261, PA, USA.; Niedernhofer LJ; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, 33458, FL, USA.; Robbins PD; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, 33458, FL, USA. probbins@scripps.edu.
Source
Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Subject
Language
English
Abstract
Aging is the main risk factor for many chronic degenerative diseases and cancer. Increased senescent cell burden in various tissues is a major contributor to aging and age-related diseases. Recently, a new class of drugs termed senolytics were demonstrated to extending healthspan, reducing frailty and improving stem cell function in multiple murine models of aging. To identify novel and more optimal senotherapeutic drugs and combinations, we established a senescence associated β-galactosidase assay as a screening platform to rapidly identify drugs that specifically affect senescent cells. We used primary Ercc1 -/- murine embryonic fibroblasts with reduced DNA repair capacity, which senesce rapidly if grown at atmospheric oxygen. This platform was used to screen a small library of compounds that regulate autophagy, identifying two inhibitors of the HSP90 chaperone family as having significant senolytic activity in mouse and human cells. Treatment of Ercc1 -/∆ mice, a mouse model of a human progeroid syndrome, with the HSP90 inhibitor 17-DMAG extended healthspan, delayed the onset of several age-related symptoms and reduced p16 INK4a expression. These results demonstrate the utility of our screening platform to identify senotherapeutic agents as well as identified HSP90 inhibitors as a promising new class of senolytic drugs.The accumulation of senescent cells is thought to contribute to the age-associated decline in tissue function. Here, the authors identify HSP90 inhibitors as a new class of senolytic compounds in an in vitro screening and show that administration of a HSP90 inhibitor reduces age-related symptoms in progeroid mice.