Cdkn1b overexpression in adult mice alters the balance between genome and tissue ageing

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.