PPAR accelerates cellular senescence by inducing p16^INK4 expression in human diploid fibroblasts

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