title: Cellular senescence mediates fibrotic pulmonary disease.
abstract: Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF lung tissue and senescent cell deletion rejuvenates pulmonary health in aged mice. Whether and how senescent cells regulate IPF or if their removal may be an efficacious intervention strategy is unknown. Here we demonstrate elevated abundance of senescence biomarkers in IPF lung, with p16 expression increasing with disease severity. We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic cocktail, dasatinib plus quercetin (DQ), is fibrogenic. Leveraging the bleomycin-injury IPF model, we demonstrate that early-intervention suicide-gene-mediated senescent cell ablation improves pulmonary function and physical health, although lung fibrosis is visibly unaltered. DQ treatment replicates benefits of transgenic clearance. Thus, our findings establish that fibrotic lung disease is mediated, in part, by senescent cells, which can be targeted to improve health and function.
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Mayo Clinic 200 First Street Southwest, Rochester, Minnesota 55905, USA.|Department of Physical Medicine and Rehabilitation, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Marissa J
authors.initials: MJ
authors.lastname: Schafer
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Mayo Clinic 200 First Street Southwest, Rochester, Minnesota 55905, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: White
authors.affiliation: Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Iijima
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Haak
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ligresti
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Atkinson
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Oberg
authors.affiliation: Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing Newcastle upon Tyne NE4 5PL, UK.
authors.forename: Jodie
authors.initials: J
authors.lastname: Birch
authors.affiliation: Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing Newcastle upon Tyne NE4 5PL, UK.
authors.forename: Hanna
authors.initials: H
authors.lastname: Salmonowicz
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Mayo Clinic 200 First Street Southwest, Rochester, Minnesota 55905, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Mayo Clinic 200 First Street Southwest, Rochester, Minnesota 55905, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Mazula
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Brooks
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Fuhrmann-Stroissnigg
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Mayo Clinic 200 First Street Southwest, Rochester, Minnesota 55905, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Pirtskhalava
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.|Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Mayo Clinic 200 First Street Southwest, Rochester, Minnesota 55905, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Tchkonia
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Marie Christine
authors.initials: MC
authors.lastname: Aubry
authors.affiliation: Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing Newcastle upon Tyne NE4 5PL, UK.
authors.forename: João F
authors.initials: JF
authors.lastname: Passos
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Mayo Clinic 200 First Street Southwest, Rochester, Minnesota 55905, USA.|Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.|Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Kirkland
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Tschumperlin
authors.affiliation: Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Kita
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Mayo Clinic 200 First Street Southwest, Rochester, Minnesota 55905, USA.|Department of Physical Medicine and Rehabilitation, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.|Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Nathan K
authors.initials: NK
authors.lastname: LeBrasseur
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001761:Bleomycin; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000473:pathology*; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D020543:Proteome / Q000378:metabolism
chemical_list: D015415:Biomarkers; D019941:Cyclin-Dependent Kinase Inhibitor p16; D020543:Proteome; D001761:Bleomycin