title: Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.
abstract: Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.
authors: Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors: Darren J
authors: DJ
authors: Baker
authors: Tobias
authors: T
authors: Wijshake
authors: Tamar
authors: T
authors: Tchkonia
authors: Nathan K
authors: NK
authors: LeBrasseur
authors: Bennett G
authors: BG
authors: Childs
authors: Bart
authors: B
authors: van de Sluis
authors: James L
authors: JL
authors: Kirkland
authors: Jan M
authors: JM
authors: van Deursen
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D000375:Aging / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002452:Cell Count; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D005123:Eye / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D005260:Female; D015870:Gene Expression; D005838:Genotype; D008136:Longevity / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D010641:Phenotype; D011371:Progeria / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D014886:Weaning
chemical_list: C463061:AP20187; C584278:Bub1b protein, mouse; C417743:Cdkn2a protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D016559:Tacrolimus