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Aging Cell. 2017 Aug;16(4):615-623. doi: 10.1111/acel.12599. Epub 2017 Apr 23.

Endoplasmic reticulum proteostasis impairment in aging.

Martínez G1,2,3,4, Duran-Aniotz C1,2,3, Cabral-Miranda F1,2,3,5, Vivar JP1,2,3, Hetz C1,2,3,6,7.

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Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.
Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.
Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
Center for Integrative Biology, Universidad Mayor, Santiago, Chile.
Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil.
Buck Institute for Research on Aging, Novato, CA, 94945, USA.
Department of Immunology and Infectious diseases, Harvard School of Public Health, Boston, MA, 02115, USA.


Perturbed neuronal proteostasis is a salient feature shared by both aging and protein misfolding disorders. The proteostasis network controls the health of the proteome by integrating pathways involved in protein synthesis, folding, trafficking, secretion, and their degradation. A reduction in the buffering capacity of the proteostasis network during aging may increase the risk to undergo neurodegeneration by enhancing the accumulation of misfolded proteins. As almost one-third of the proteome is synthetized at the endoplasmic reticulum (ER), maintenance of its proper function is fundamental to sustain neuronal function. In fact, ER stress is a common feature of most neurodegenerative diseases. The unfolded protein response (UPR) operates as central player to maintain ER homeostasis or the induction of cell death of chronically damaged cells. Here, we discuss recent evidence placing ER stress as a driver of brain aging, and the emerging impact of neuronal UPR in controlling global proteostasis at the whole organismal level. Finally, we discuss possible therapeutic interventions to improve proteostasis and prevent pathological brain aging.


aging; endoplasmic reticulum; endoplasmic reticulum stress; protein misfolding disorders; unfolded protein response

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