ΔNp63α overexpression induces downregulation of Sirt1 and an accelerated aging phenotype in the mouse

p63 is highly expressed in the skin and appears to be an early marker of keratinocyte differentiation. To examine the role of p63 in vivo, we generated transgenic mice that overexpress Delta Np63 alpha in the skin. These mice exhibited an accelerated aging phenotype in the skin characterized by striking wound healing defects, decreased skin thickness, decreased subcutaneous fat tissue, hair loss, and decreased cell proliferation. The accelerated skin aging was accompanied by a dramatic decrease in longevity of the mice. We found that aging in Delta Np63 alpha transgenic mice and other mouse models correlated with levels of Sirt1, a mammalian SIR2 orthologue thought to extend the lifespan in lower species. Moreover, increased Delta Np63 alpha expression induced cellular senescence that was rescued by Sirt1. Our data suggest that Delta Np63 alpha levels may affect aging in mammals, at least in part, through regulation of Sirt1.