The endoplasmic reticulum (ER) is a crucial organelle in the cell where protein folding and processing occurs, and conditions that negatively affect ER functions are highly detrimental to the cell. The accumulation of unfolded/misfolded proteins in the ER leads to a condition known as ER Stress. The ER has developed various pro-survival and pro-apoptosis signaling pathways that attempt to cope with this stress. ER stress is relevant to many clinical studies and has been linked to a variety of age-related diseases, including Huntington’s, Alzheimer’s, Parkinson’s and heart disease. Despite these findings, the manner in which ER stress response is altered with age hasn’t been thoroughly studied and constitutes a gap in knowledge. In this study, we investigated the age-related loss of ER stress response in young and old rats. Our results suggest that, in both young and old cells, the pro-apoptosis pathway which utilizes the transcription factor, CHOP, remains intact with age. However, the pro-survival pathway acting through PERK/Nrf2 and the phase II detoxification enzyme NQO1 show elevated activity in the young cells, but a loss of function in the old. These results suggest that stresses which would not cause cell death in young individuals may induce cell death in the elderly.