Reduced eIF2α phosphorylation and increased proapoptotic proteins in aging

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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.

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Materials

Wistar rats were kept under standard conditions of light and temperature and fed ad libitum access on commercial rat chow and water. All experiments were carried out according to the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India, guidelines. The antibodies are obtained from Cell Signaling Technologies (eIF4E, phospho-eIF4E, phospho-4EBP’s, S6, and phospho-S6), Research Genetics (phospho-eIF2α), Calbiochem (GRP-78/BiP), Sigma

Initiation factors and their phosphorylation are reduced during aging

Relative levels of several eukaryotic initiation factors (eIFs) viz., eIF2α, eIF2Bε, eIF5, eIF4E (Fig. 1), and S6, a 40S ribosomal protein (Fig. 1), and also the phosphorylation of eIF2α, eIF4E, S6, and eIF4E binding proteins (eIF4E BPs) (Fig. 2) reduced during aging in different rat tissues. The reduction in the abundance of ribosomes as measured from S6 levels and in translational factors during aging is consistent with the previous observations that translation decreases with aging [1], [25]

Acknowledgments

K.V.A.R. thanks ICMR, New-Delhi for financial support of a Project 52/6/99-BMS and S.H. thanks UGC for a fellowship.

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