title: Cdkn1b overexpression in adult mice alters the balance between genome and tissue ageing.
abstract: Insufficient cell proliferation has been suggested as a potential cause of age-related tissue dysgenesis in mammals. However, genetic manipulation of cell cycle regulators in the germ lines of mice results in changes in animal size but not progeroid phenotypes. Here we increase levels of the cyclin-dependent kinase inhibitor Cdkn1b (p27kip1) in adult mice through doxycycline-inducible expression and show this results in reduced cell proliferation in multiple tissues. The mice undergo changes resembling ageing even in the absence of an elevated DNA damage response or evidence of senescent cells, suggesting an altered balance between genetic and tissue ageing. In contrast, suppressing cell proliferation by doxycycline treatment of neonates retards growth, but the onset of degenerative changes is delayed during the period of reduced body mass. These results support the hypothesis that many of the most recognizable features of mammalian ageing can result from an imbalance between cell production and the mass of tissue that must be maintained.
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Pruitt
authors.forename: Amy
authors.initials: A
authors.lastname: Freeland
authors.forename: Michael E
authors.initials: ME
authors.lastname: Rusiniak
authors.forename: Dimiter
authors.initials: D
authors.lastname: Kunnev
authors.forename: Gillian K
authors.initials: GK
authors.lastname: Cady
mesh_terms: D000375:Aging / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D015870:Gene Expression; D016678:Genome; D051379:Mice; D008822:Mice, Transgenic; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: C493961:Cdkn1b protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004318:Doxycycline