title: Reversible cell cycle inhibition and premature aging features imposed by conditional expression of p16Ink4a.
abstract: The cyclin-dependent kinase (Cdk) inhibitor p16(Ink4a) (p16) is a canonical mediator of cellular senescence and accumulates in aging tissues, where it constrains proliferation of some progenitor cells. However, whether p16 induction in tissues is sufficient to inhibit cell proliferation, mediate senescence, and/or impose aging features has remained unclear. To address these issues, we generated transgenic mice that permit conditional p16 expression. Broad induction at weaning inhibited proliferation of intestinal transit-amplifying and Lgr5+ stem cells and rapidly imposed features of aging, including hair loss, skin wrinkling, reduced body weight and subcutaneous fat, an increased myeloid fraction in peripheral blood, poor dentition, and cataracts. Aging features were observed with multiple combinations of p16 transgenes and transactivators and were largely abrogated by a germline Cdk4 R24C mutation, confirming that they reflect Cdk inhibition. Senescence markers were not found, and de-induction of p16, even after weeks of sustained expression, allowed rapid recovery of intestinal cell proliferation and reversal of aging features in most mice. These results suggest that p16-mediated inhibition of Cdk activity is sufficient to inhibit cell proliferation and impose aging features in somatic tissues of mammals and that at least some of these aging features are reversible.
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA; Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Amelie
authors.initials: A
authors.lastname: Boquoi
authors.forename: Sanjeevani
authors.initials: S
authors.lastname: Arora
authors.forename: Tina
authors.initials: T
authors.lastname: Chen
authors.forename: Sam
authors.initials: S
authors.lastname: Litwin
authors.forename: James
authors.initials: J
authors.lastname: Koh
authors.forename: Greg H
authors.initials: GH
authors.lastname: Enders
mesh_terms: D019588:Aging, Premature / Q000473:pathology*; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology; D006801:Humans; D007422:Intestines / Q000166:cytology; D008822:Mice, Transgenic; D015203:Reproducibility of Results; D013234:Stem Cells / Q000166:cytology
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D051358:Cyclin-Dependent Kinase 4
keywords: Cdk; Ink4a; aging; p16; senescence; stem cell