A decline in relative levels and phosphorylation of many of the eukaryotic initiation factors (eIFs) including S6, the 40S ribosomal subunit protein in many of the rat tissues during chronological aging is accompanied by elevated levels of eIF2 alpha kinases, such as PKR and PERK, but not their activity. Concomitant with increased eIF2 alpha phosphorylation, young tissues displayed a higher level of eIF2B to tolerate the toxic effect of eIF2 alpha phosphorylation on translation, ATF4, a b-zip transcriptional factor that is produced as part of the gene expression programe in response to eIF2 alpha phosphorylation, and BiP, an endoplasmic reticulum (ER) molecular chaperone and regulator of ER stress sensors. Decline in eIF2 alpha phosphorylation in aged tissues is associated with a higher level of GADD34, a subunit of eIF2 alpha phosphatase, and proapoptotic proteins like CHOP/GADD153 and phospho JNK, suggesting that young tissues possess an efficient ER stress adaptive mechanism that declines with aging. (c) 2007 Elsevier Inc. All rights reserved.