PPARγ accelerates cellular senescence by inducing p16INK4α expression in human diploid fibroblasts

Peroxisome proliferator-activated receptor gamma ( PPAR gamma) plays an important role in the inhibition of cell growth by promoting cell-cycle arrest, and PPAR gamma activation induces the expression of p16(INK4 alpha) ( CDKN2A), an important cell-cycle inhibitor that can induce senescence. However, the role of PPAR gamma in cellular senescence is unknown. Here, we show that PPAR gamma promotes cellular senescence by inducing p16(INK4 alpha) expression. We found several indications that PPAR gamma accelerates cellular senescence, including enhanced senescence-associated ( SA)-beta-galactosidase staining, increased G1 arrest and delayed cell growth in human fibroblasts. Western blotting studies demonstrated that PPAR gamma activation can upregulate the expression of p16(INK4 alpha). PPAR gamma can bind to the p16 promoter and induce its transcription, and, after treatment with a selective PPAR gamma agonist, we observed more-robust expression of p16(INK4 alpha) in senescent cells than in young cells. In addition, our data indicate that phosphorylation of PPAR gamma decreased with increased cell passage. Our results provide a possible molecular mechanism underlying the regulation of cellular senescence.