p19(ARF) plays an essential role in the senescence of mouse cells, and its 
expression is lost by methylation or deletion of the ARF locus; otherwise, p53 
is inactivated to bypass senescence. ARF expression is tightly regulated, but 
little is known about its posttranscriptional regulation. Here, we show that an 
RNA-binding protein, HuR (human antigen R), represses ARF mRNA translation, 
thereby maintaining the replicative life span of mouse embryonic fibroblasts 
(MEFs). Loss of HuR results in premature senescence, with concomitant increases 
in p19(ARF) but not p16(Ink4a) levels, and this senescence is not observed in 
ARF-null MEFs that retain an intact Ink4a locus. HuR depletion does not alter 
ARF transcription or stability but enhances ribosome association with ARF mRNA. 
Under these conditions, ARF mRNA accumulates in nucleoli, where it associates 
with nucleolin. Furthermore, adipose-specific deletion of the HuR gene results 
in increased p19(ARF) expression in aged animals, which is accompanied by 
decreased insulin sensitivity. Together, our findings demonstrate that p19(ARF) 
is also regulated at the translational level, and this translational regulation 
restrains the cellular life span and tissue functions in vivo.