Akt/PKB and p38 MAPK signaling, translational initiation and longevity in Snell dwarf mouse livers.

The insulin/IGF-1/GH and p38 MAPK signaling pathways play a key role in the regulation of protein synthesis. The regulation of GH and TSH secretion hormones, that affect the activity of these pathways, plays an important role in the decline of rates of protein synthesis in aged rodent tissues. Studies have indicated that longevity of the Snell dwarf (Pit-1) mouse mutant is associated with the reduction of function of the insulin/IGF-1/GH signaling pathway. We have previously shown that PI3K activity, a signaling protein that plays a key role in the regulation of translation, is also dramatically decreased in the Snell dwarf liver suggesting that the protein synthesis-signaling pathway may be attenuated in this long-lived mouse. Similarly, signaling via p38 MAPK also plays a role in the regulation of protein synthesis. In this study we examined the activities of these signaling pathways to determine if the translation-signaling pathway is altered in young versus aged Snell dwarf mouse livers. Our data indicate that the phosphorylation and kinase activities of Akt/PKB and p38 MAPK, and the levels of phosphorylation of downstream regulators of translation are decreased in dwarf mouse livers. Thus, the overall activities of major components of the translational initiation pathway are decreased in the long-lived Snell dwarf mouse livers. We propose that down-regulation of protein synthesis may be an important characteristic of the Pit-1 mutation and longevity of the Snell dwarf mouse.