In vivo analysis of gene expression in long-lived mice lacking the pregnancy-associated plasma protein A (PappA) gene.

Mice lacking the pregnancy-associated plasma protein A (PappA) gene exhibit diminished localized IGF-1 bioavailability and a 30% increase in mean life span. However, it is uncertain which tissues exhibit reduced IGF-1 signals in the PappA(-/-) mouse, and whether effects of this mutation parallel those of mutations that diminish IGF-1 in serum. Across a panel of 21 tissues, we used RT-PCR to evaluate the effects of the PappA(-/-) mutation on expression of Igfbp5, which served as an in vivo indicator of IGF-1 signaling. Among these tissues, expression of Igfbp5 was significantly reduced by PappA(-/-) only in kidney. A broader survey of IGF-associated genes in six organs identified five other genes responsive to PappA(-/-) in kidney, with stronger effects in this organ relative to other tissues. Renal expression of Irs1 and Mt1 was increased by PappA(-/-) as well as by mutations that reduce IGF-1 in serum (i.e., Ghr(-/-), Pit1(dw/dw) and Prop1(df/df)), and we demonstrate that expression of these genes is regulated by growth hormone-treatment and calorie restriction. These results provide in vivo data on an important new model of mammalian aging, and characterize both similar and contrasting expression patterns between long-lived mice with reduced local IGF-1 availability and diminished IGF-1 in serum.