The misfolding, aggregation, and tissue accumulation of proteins are common events in diverse chronic diseases, known as protein misfolding disorders. Many of these diseases are associated with aging, but the mechanism for this connection is unknown. Recent evidence has shown that the formation and accumulation of protein aggregates may be a process frequently occurring during normal aging, but it is unknown whether protein misfolding is a cause or a consequence of aging. To combat the formation of these misfolded aggregates cells have developed complex and complementary pathways aiming to maintain protein homeostasis. These protective pathways include the unfolded protein response, the ubiquitin proteasome system, autophagy, and the encapsulation of damaged proteins in aggresomes. In this paper we review the current knowledge on the role of protein misfolding in disease and aging as well as the implication of deficiencies in the proteostasis cellular pathways in these processes. It is likely that further understanding of the mechanisms involved in protein misfolding and the natural defense pathways may lead to novel strategies for treatment of age-dependent protein misfolding disorders and perhaps aging itself. 1. Introduction Multiple and complex biological processes occur simultaneously in living cells. These processes must be strictly regulated in order to allow an optimal equilibrium and function. Proteins are key macromolecules, which perform a vast array of functions within living organisms, including replicating genetic material, catalyzing metabolic reactions, maintaining the cellular structure, participating in cellular signaling, immune responses, cell adhesion, cell cycle, responding to stimuli, and transporting molecules from one location to another. Life depends on the proper function of thousands of proteins, which in turn depends upon the acquisition of the correct, biologically functional folding of the protein. The cellular processes responsible for the synthesis, folding, and turnover of proteins are known as protein homeostasis or proteostasis [1]. The proteostasis network controls protein concentration, subcellular location, folding through molecular chaperone systems and folding enzymes, protein degradation mediated by the proteasome, lysosome, and autophagy, among others. Defects of proteostasis may commonly lead to aberrant folding, aggregation, and accumulation of proteins resulting in cellular damage and tissue dysfunction. 2. Protein Misfolding in Disease Currently there are at least 30 different human diseases reported to be
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