Opposing roles for p16 Ink4a and p19 Arf in senescence and ageing caused by BubR1 insufficiency

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.