Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency

Abstract

Expression of p16^Ink4a and p19^Arf increases with age in both rodent and human tissues. However, whether these tumour suppressors are effectors of ageing remains unclear, mainly because knockout mice lacking p16^Ink4a or p19^Arf die early of tumours. Here, we show that skeletal muscle and fat, two tissues that develop early ageing-associated phenotypes in response to BubR1 insufficiency, have high levels of p16^Ink4a and p19^Arf. Inactivation of p16^Ink4a in BubR1-insufficient mice attenuates both cellular senescence and premature ageing in these tissues. Conversely, p19^Arf inactivation exacerbates senescence and ageing in BubR1 mutant mice. Thus, we identify BubR1 insufficiency as a trigger for activation of the Cdkn2a locus in certain mouse tissues, and demonstrate that p16^Ink4a is an effector and p19^Arf an attenuator of senescence and ageing in these tissues.