title: Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan.
abstract: Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16(Ink4a)-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16(Ink4a)-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16(Ink4a)-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.
authors: Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors: Darren J
authors: DJ
authors: Baker
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors: Bennett G
authors: BG
authors: Childs
authors: Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors: Matej
authors: M
authors: Durik
authors: Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors: Melinde E
authors: ME
authors: Wijers
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors: Cynthia J
authors: CJ
authors: Sieben
authors: Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors: Jian
authors: J
authors: Zhong
authors: Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors: Rachel A
authors: RA
authors: Saltness
authors: Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors: Karthik B
authors: KB
authors: Jeganathan
authors: Division of Cardiovascular Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors: Grace Casaclang
authors: GC
authors: Verzosa
authors: Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors: Abdulmohammad
authors: A
authors: Pezeshki
authors: Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors: Khashayarsha
authors: K
authors: Khazaie
authors: Division of Cardiovascular Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors: Jordan D
authors: JD
authors: Miller
authors: Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.|Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors: Jan M
authors: JM
authors: van Deursen
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000473:pathology / Q000502:physiology; D000375:Aging / Q000473:pathology* / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D016922:Cellular Senescence / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000473:pathology; D005260:Female; D006262:Health; D007668:Kidney / Q000166:cytology / Q000473:pathology / Q000502:physiology / Q000503:physiopathology; D008060:Lipodystrophy / Q000473:pathology; D008136:Longevity / Q000502:physiology*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D013234:Stem Cells / Q000166:cytology / Q000473:pathology; D013997:Time Factors
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16