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Proteostasis and Aging PERSPECTIVE FOCUS ON AGI N G Proteostasis and aging Susmita Kaushik & Ana Maria Cuervo Accumulation of intracellular damage is an almost universal of the proteostasis networks in invertebrates and in mammals hallmark of aging. An improved understanding of the systems extend their lifespans and healthspans1,3,4. that contribute to cellular protein quality control has shed light A detailed description of each of the systems that maintains cellular on the reasons for the increased vulnerability of the proteome proteostasis is beyond the scope of this Perspective. Here we focus to stress in aging cells. Maintenance of protein homeostasis, on the recognized importance of the loss of proteostasis in aging. or proteostasis, is attained through precisely coordinated We first describe specific characteristics of the proteostasis networks systems that rapidly correct unwanted proteomic changes. that make these systems vulnerable to the chronic stress that is often Here we focus on recent developments that highlight the associated with aging. Then we touch upon newly identified dimen- multidimensional nature of the proteostasis networks, which sions of the proteostasis networks, beyond the relatively well-known allow for coordinated protein homeostasis intracellularly, cellular cytoplasm, that have transformed the ways in which we in between cells and even across organs, as well as on think about proteostasis. This includes concepts such as organelle how they affect common age-associated diseases when they proteostasis, organ or tissue proteostasis and even organism pro- malfunction in aging. teostasis networks that help to integrate a coordinated proteostatic response throughout the whole body. We argue that this integrated Protein homeostasis, or proteostasis, is assured through the coordi- view of proteostasis is of utmost relevance to further understand the nated action of intricate cellular systems—the proteostasis networks. basis and consequences of a loss of proteostasis in aging and that it Under normal conditions, these systems rapidly sense and rectify has generated considerable interest as a yet-unexplored therapeutic disturbances in the proteome to restore basal homeostasis1. During target for the treatment of age-related diseases. stress, similar systems preserve proteome solubility and functionality by bringing it to an altered point of proteostasis balance that takes into Aging of the components of proteostasis systems Nature America, Inc. All rights reserved. America, Inc. Nature consideration the stress-induced cellular changes2. The main players in proteostasis maintenance are chaperones and 5 Although the robustness and adaptability of the proteostasis net- two proteolytic systems, the ubiquitin-proteasome and the lysosome- © 201 works is remarkable, if stressors are chronic, the proteostasis balance autophagy systems (Fig. 1). These components decide the fate of becomes difficult to maintain, and proteotoxicity develops3. With unfolded proteins: whether they will refold into their original stable age, the ability of many cells and organs to preserve proteostasis conformation or whether they will instead be eliminated from the under resting and stress conditions is gradually compromised4. Loss cell through proteolysis8. npg of proteostasis is part of the pathogenesis of many human patholo- gies, including neurodegenerative diseases such as Alzheimer’s disease Chaperones. Chaperones assist proteins through each of the different or Parkinson’s disease3. It is not a coincidence that many of these conformational changes that they undergo during their lifetime, which diseases—generically known as proteinopathies or protein confor- include de novo folding, assembly and disassembly, transport across mational diseases—are regarded as age-related disorders, given that membranes and targeting for degradation9. The need for chaperones the physiological deterioration of the proteostasis networks with age originates from the crowded environment in the cytoplasm as well as is an important aggravating factor in these diseases1,4,5. in the lumen of most organelles. An important aspect of chaperone Numerous lines of evidence support a tight relationship between functioning is the molecules’ ability to integrate multiple cellular cues proteostasis and healthy aging. Although a gradual loss of proteos- in order to decide the fate of cellular proteins that have lost their stable tasis can be detected in most organisms as they age, the longest- conformations. Thus, even for proteins that have experienced the same living species have been shown to have more stable proteomes6 degree of unfolding, chaperones will assist them to either refold or (comprised of cellular proteins that are more resistant to damage), degrade, depending on the feasibility of the cell doing one or the other and, for example, in the case of the long-lived naked mole rat, pro- at that particular time. Factors such as cellular ATP content (because teome stability correlates with enhanced activity in the proteostasis substrate binding and release requires ATP hydrolysis), as well as over- systems7. Furthermore, interventions that modulate the activity all chaperone availability, may also contribute to this final decision. Once a commitment to degradation is made, chaperones often also Department of Developmental and Molecular Biology, Institute for Aging Studies, decide the proteolytic pathway that each misfolded protein will follow. Albert Einstein College of Medicine, New York, New York, USA. Correspondence For example, HSC70, a constitutive cellular chaperone, can target pro- should be addressed to A.M.C. ([email protected]) teins for degradation. The two systems most commonly used for this Received 20 September; accepted 2 November; published online 8 December breakdown of proteins are the proteasome and autophagy systems. 2015; doi:10.1038/nm.4001 The proteasome, a multi-subunit protease that is most abundant in 1406 VOLUME 21 | NUMBER 12 | DECEMBER 2015 NATURE MEDICINE PERSPECTIVE Figure 1 Changes with age in intracellular proteostasis systems. Chaperones and two proteolytic systems, the ubiquitin proteasome UPS activity UPS system (UPS) and autophagy, take care of Ubiquitination maintenance of intracellular proteostasis. Subunit levels Exosome Chaperones (blue, yellow and gray circles) assist Assembly Chaperones de novo synthesized proteins and unfolded proteins to reach their folded stable status. Proteasome If folding is not possible, chaperones target the unfolded protein for degradation by the proteasome (often after ubiquitination) or in lysosomes. Single soluble proteins can reach the CMA activity Multivesicular body or L2A levels lysosomal lumen through a membrane transporter late endosome CMA in chaperone-mediated autophagy (CMA). Once misfolded proteins organize into oligomers HSC70 or insoluble aggregates, the only options for their elimination from the cytosol are either by Protein Folded protein Misfolded protein L2A degradation in lysosomes through macroautophagy synthesis Lysosome (MA) or expulsion outside the cell by means of Macroautophagy small vesicles (exosomes). Red boxes indicate Chaperone changes with age in different steps or components depletion of the intracellular proteostasis networks. Ribosome APG-LYS, autophagosome-lysosome; HSC70, heat-shock cognate protein of 70kDa; L2A, Aggregate lysosome-associated membrane protein type 2A. Autophagosome Aggregates MA activity Cargo recognition Phagophore induction the cytosol—although it can also be detected APG-LYS fusion in the nucleus—is responsible for the rapid Debbie Maizels/Nature Publishing Group degradation of proteins that are often tagged with covalently attached strands of the small protein ubiquitin10,11. the substrate protein can also interfere with the chaperone’s ability Proteins can also be degraded in lysosomes through a process known to recognize its target. For example, the accumulation with aging as autophagy. Different types of autophagy have been identified of advanced glycation end-products through non-enzymatic modi- (macroautophagy, microautophagy and chaperone-mediated fications on long-lived proteins interferes with normal chaperone autophagy), and the choice of which to use depends on how the function. This type of modification is amenable to repair by enzymes proteins are identified and delivered to lysosomes12 (Fig. 1). The such as methionine sulfoxide reductase, but the abundance of these association of other chaperones and co-chaperones, such as CHIP enzymes decreases with age, further contributing to an accumulation Nature America, Inc. All rights reserved. America, Inc. Nature 20 5 or BAG3, with HSC70 determines HSC70-mediated targeting of of altered proteins that are unrecognizable to chaperones . Cells proteins through degradation by the proteasome and macroautophagy, may accommodate some of these age-related changes by modifying © 201 respectively. Properties in the cargo protein also contribute to the the pool of chaperones involved in proteostasis. Thus, although the selection of the degradation pathway. For example, although single HSP70 and HSP90 heat-shock protein families of chaperones have unfolded proteins can be eliminated through almost any degradation well-recognized roles in proteome balance under normal conditions, pathway, once multiple proteins organize into oligomeric complexes recent studies in nematodes highlight a prominent function of small npg or aggregates, they can only be degraded by means of a selective form heat-shock
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