Introduction: Proteostasis is the ability of the cell to balance folding nascent proteins with degrading terminally misfolded ones. A major site of proteostasis in the cardiac myocyte is the endoplasmic reticulum (ER), the location of the majority of protein synthesis, folding, and trafficking. In response to increased protein folding demand or stresses such as chronic ischemia, cardiac myocytes maintain proteostasis by activating the unfolded protein response (UPR). Our lab has established that the transcription factor ATF6 regulates the adaptive branch of the UPR and confers protection in the heart by upregulating a protective gene panel. As the incidence of cardiovascular diseases associated with impaired proteostasis increases with age, it is imperative to elucidate the role of ATF6 as a function of age. Hypothesis: ATF6 and its transcriptional targets are downregulated with age thereby increasing susceptibility to proteotoxic imbalance and cardiac myocyte death. Methods: To assess basal expression of ATF6 and its transcriptional targets as a function of age, ventricular tissue from mice at P1, 10-weeks, and 52-weeks of age were subjected to quantitative RT-PCR. To measure responsiveness to proteotoxic stress, mice at all age groups were treated with an inducer of the UPR, tunicamycin (TM) for 24 hours, followed by transcriptional profiling. These experiments were repeated in isolated ventricular myocytes from all age groups to assess comparative viability. To recapitulate any phenotype observed in 10-week and 52-week myocytes, ATF6 was knocked down in P1 isolated myocytes. Results: Basal ATF6 expression was coordinately downregulated as a function of age in hearts from mice at P1, 10-weeks, and 52-weeks as was their responsiveness to administration of TM. This phenotype was similarly observed in isolated myocytes from all age groups along with an age-associated decrease in myocyte viability in response to TM. Knocking down ATF6 in P1 isolated myocytes perpetuated cell death thereby simulating the phenotype of an old myocyte in a young myocyte. Conclusion: ATF6 and its adaptive transcriptional targets are downregulated with age, promoting an increased susceptibility to proteotoxic-mediated cardiac myocyte death. We posit that restoration of ATF6 presents a novel therapeutic avenue for treatment of conditions with increased proteotoxic stress.