Reduced eIF2α phosphorylation and increased proapoptotic proteins in aging

Abstract

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 eIF2α kinases, such as PKR and PERK, but not their activity. Concomitant with increased eIF2α phosphorylation, young tissues displayed a higher level of eIF2B to tolerate the toxic effect of eIF2α phosphorylation on translation, ATF4, a b-zip transcriptional factor that is produced as part of the gene expression programe in response to eIF2α phosphorylation, and BiP, an endoplasmic reticulum (ER) molecular chaperone and regulator of ER stress sensors. Decline in eIF2α phosphorylation in aged tissues is associated with a higher level of GADD34, a subunit of eIF2α 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.