Abstract
Accumulation of intracellular damage is an almost universal hallmark of aging. An improved understanding of the systems that contribute to cellular protein quality control has shed light on the reasons for the increased vulnerability of the proteome to stress in aging cells. Maintenance of protein homeostasis, or proteostasis, is attained through precisely coordinated systems that rapidly correct unwanted proteomic changes. Here we focus on recent developments that highlight the multidimensional nature of the proteostasis networks, which allow for coordinated protein homeostasis intracellularly, in between cells and even across organs, as well as on how they affect common age-associated diseases when they malfunction in aging.
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References
Vilchez, D., Saez, I. & Dillin, A. The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nat. Commun. 5, 5659 (2014).
Roth, D.M. & Balch, W.E. Modeling general proteostasis: proteome balance in health and disease. Curr. Opin. Cell Biol. 23, 126–134 (2011).
Morimoto, R.I. & Cuervo, A.M. Proteostasis and the aging proteome in health and disease. J. Gerontol. A Biol. Sci. Med. Sci. 69 (suppl. 1), S33–S38 (2014).
Labbadia, J. & Morimoto, R.I. The biology of proteostasis in aging and disease. Annu. Rev. Biochem. 84, 435–464 (2015).
Labbadia, J. & Morimoto, R.I. Proteostasis and longevity: when does aging really begin? F1000Prime Rep. 6, 7 (2014).
Treaster, S.B. et al. Superior proteome stability in the longest lived animal. Age (Dordr) 36, 9597 (2014).
Pérez, V.I. et al. Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat. Proc. Natl. Acad. Sci. USA 106, 3059–3064 (2009).
Tyedmers, J., Mogk, A. & Bukau, B. Cellular strategies for controlling protein aggregation. Nat. Rev. Mol. Cell Biol. 11, 777–788 (2010).
Feldman, D.E. & Frydman, J. Protein folding in vivo: the importance of molecular chaperones. Curr. Opin. Struct. Biol. 10, 26–33 (2000).
Navon, A. & Ciechanover, A. The 26 S proteasome: from basic mechanisms to drug targeting. J. Biol. Chem. 284, 33713–33718 (2009).
Tanaka, K. The proteasome: overview of structure and functions. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 85, 12–36 (2009).
Kaushik, S. & Cuervo, A.M. Chaperones in autophagy. Pharmacol. Res. 66, 484–493 (2012).
Lamark, T. & Johansen, T. Aggrephagy: selective disposal of protein aggregates by macroautophagy. Int. J. Cell Biol. 2012, 736905 (2012).
Arndt, V. et al. Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr. Biol. 20, 143–148 (2010).
Stolz, A., Ernst, A. & Dikic, I. Cargo recognition and trafficking in selective autophagy. Nat. Cell Biol. 16, 495–501 (2014).
Ma, Y. & Li, J. Metabolic shifts during aging and pathology. Compr. Physiol. 5, 667–686 (2015).
Ritz, P. & Berrut, G. Mitochondrial function, energy expenditure, aging and insulin resistance. Diabetes Metab. 31 (spec. no. 2), 5S67–5S73 (2005).
Brehme, M. et al. A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease. Cell Rep. 9, 1135–1150 (2014).
Yu, A. et al. Protein aggregation can inhibit clathrin-mediated endocytosis by chaperone competition. Proc. Natl. Acad. Sci. USA 111, E1481–E1490 (2014).
Vanhooren, V. et al. Protein modification and maintenance systems as biomarkers of ageing. Mech. Ageing Dev. doi:10.1016/j.mad.2015.03.009 (2015).
Morrow, G., Samson, M., Michaud, S. & Tanguay, R.M. Overexpression of the small mitochondrial Hsp22 extends Drosophila life span and increases resistance to oxidative stress. FASEB J. 18, 598–599 (2004).
Walther, D.M. et al. Widespread proteome remodeling and aggregation in aging C. elegans. Cell 161, 919–932 (2015).
Rubinsztein, D.C., Marino, G. & Kroemer, G. Autophagy and aging. Cell 146, 682–695 (2011).
Chondrogianni, N., Georgila, K., Kourtis, N., Tavernarakis, N. & Gonos, E.S. 20S proteasome activation promotes life span extension and resistance to proteotoxicity in Caenorhabditis elegans. FASEB J. 29, 611–622 (2015).
Madeo, F., Zimmermann, A., Maiuri, M.C. & Kroemer, G. Essential role for autophagy in life span extension. J. Clin. Invest. 125, 85–93 (2015).
Pyo, J.O. et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat. Commun. 4, 2300 (2013).
Morton, J.P., Kayani, A.C., McArdle, A. & Drust, B. The exercise-induced stress response of skeletal muscle, with specific emphasis on humans. Sports Med. 39, 643–662 (2009).
Ulbricht, A. et al. Induction and adaptation of chaperone-assisted selective autophagy CASA in response to resistance exercise in human skeletal muscle. Autophagy 11, 538–546 (2015).
He, C. et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511–515 (2012).
Jamart, C. et al. Modulation of autophagy and ubiquitin-proteasome pathways during ultra-endurance running. J. Appl. Physiol. 112, 1529–1537 (2012).
Katsiki, M., Chondrogianni, N., Chinou, I., Rivett, A.J. & Gonos, E.S. The olive constituent oleuropein exhibits proteasome stimulatory properties in vitro and confers life span extension of human embryonic fibroblasts. Rejuvenation Res. 10, 157–172 (2007).
Salomone, F. et al. Coffee enhances the expression of chaperones and antioxidant proteins in rats with nonalcoholic fatty liver disease. Transl. Res. 163, 593–602 (2014).
Ben-Zvi, A., Miller, E.A. & Morimoto, R.I. Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging. Proc. Natl. Acad. Sci. USA 106, 14914–14919 (2009).
Iram, A. & Naeem, A. Protein folding, misfolding, aggregation and their implications in human diseases: discovering therapeutic ways to amyloid-associated diseases. Cell Biochem. Biophys. 70, 51–61 (2014).
Kim, Y.E., Hipp, M.S., Bracher, A., Hayer-Hartl, M. & Hartl, F.U. Molecular chaperone functions in protein folding and proteostasis. Annu. Rev. Biochem. 82, 323–355 (2013).
Park, C. & Cuervo, A.M. Selective autophagy: talking with the UPS. Cell Biochem. Biophys. 67, 3–13 (2013).
Korolchuk, V.I., Menzies, F.M. & Rubinsztein, D.C. Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems. FEBS Lett. 584, 1393–1398 (2010).
Kaushik, S., Massey, A., Mizushima, N. & Cuervo, A.M. Constitutive activation of chaperone-mediated autophagy in cells with impaired macroautophagy. Mol. Biol. Cell 19, 2179–2192 (2008).
Massey, A.C., Kaushik, S., Sovak, G., Kiffin, R. & Cuervo, A.M. Consequences of the selective blockage of chaperone-mediated autophagy. Proc. Natl. Acad. Sci. USA 103, 5805–5810 (2006).
Gavilán, E. et al. Age-related dysfunctions of the autophagy lysosomal pathway in hippocampal pyramidal neurons under proteasome stress. Neurobiol. Aging 36, 1953–1963 (2015).
Schneider, J.L. et al. Loss of hepatic chaperone-mediated autophagy accelerates proteostasis failure in aging. Aging Cell 14, 249–264 (2015).
Rodríguez-Muela, N. et al. Balance between autophagic pathways preserves retinal homeostasis. Aging Cell 12, 478–488 (2013).
Tsvetkov, P. et al. Compromising the 19S proteasome complex protects cells from reduced flux through the proteasome. eLIFE 4 doi:10.7554/eLife.08467 (2015).
Walter, P. & Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086 (2011).
Brodsky, J.L. Cleaning up: ER-associated degradation to the rescue. Cell 151, 1163–1167 (2012).
Khaminets, A. et al. Regulation of endoplasmic reticulum turnover by selective autophagy. Nature 522, 354–358 (2015).
Moreno, J.A. et al. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci. Transl. Med. 5, 206ra138 (2013).
Cao, S.S. & Kaufman, R.J. Targeting endoplasmic reticulum stress in metabolic disease. Expert Opin. Ther. Targets 17, 437–448 (2013).
Hou, N.S. et al. Activation of the endoplasmic reticulum unfolded protein response by lipid disequilibrium without disturbed proteostasis in vivo. Proc. Natl. Acad. Sci. USA 111, E2271–E2280 (2014).
Satpute-Krishnan, P. et al. ER stress-induced clearance of misfolded GPI-anchored proteins via the secretory pathway. Cell 158, 522–533 (2014).
Lemasters, J.J. Variants of mitochondrial autophagy: Types 1 and 2 mitophagy and micromitophagy (Type 3). Redox Biol. 2, 749–754 (2014).
Heo, J.M. et al. A stress-responsive system for mitochondrial protein degradation. Mol. Cell 40, 465–480 (2010).
Braun, R.J. et al. Accumulation of basic amino acids at mitochondria dictates the cytotoxicity of aberrant ubiquitin. Cell Rep. 10, 1557–1571 (2015).
Jovaisaite, V. & Auwerx, J. The mitochondrial unfolded protein response-synchronizing genomes. Curr. Opin. Cell Biol. 33, 74–81 (2015).
Haynes, C.M. & Ron, D. The mitochondrial UPR - protecting organelle protein homeostasis. J. Cell Sci. 123, 3849–3855 (2010).
Jensen, M.B. & Jasper, H. Mitochondrial proteostasis in the control of aging and longevity. Cell Metab. 20, 214–225 (2014).
McDonnell, E., Peterson, B.S., Bomze, H.M. & Hirschey, M.D. SIRT3 regulates progression and development of diseases of aging. Trends Endocrinol. Metab. 26, 486–492 (2015).
Mohrin, M. et al. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 347, 1374–1377 (2015).
Shibata, Y. & Morimoto, R.I. How the nucleus copes with proteotoxic stress. Curr. Biol. 24, R463–R474 (2014).
Andersen, J.S. et al. Nucleolar proteome dynamics. Nature 433, 77–83 (2005).
Janer, A. et al. PML clastosomes prevent nuclear accumulation of mutant ataxin-7 and other polyglutamine proteins. J. Cell Biol. 174, 65–76 (2006).
Ullrich, O. et al. Poly-ADP ribose polymerase activates nuclear proteasome to degrade oxidatively damaged histones. Proc. Natl. Acad. Sci. USA 96, 6223–6228 (1999).
Lam, Y.W., Lamond, A.I., Mann, M. & Andersen, J.S. Analysis of nucleolar protein dynamics reveals the nuclear degradation of ribosomal proteins. Curr. Biol. 17, 749–760 (2007).
Iwata, A. et al. Intranuclear degradation of polyglutamine aggregates by the ubiquitin-proteasome system. J. Biol. Chem. 284, 9796–9803 (2009).
Tan, K. et al. Mitochondrial SSBP1 protects cells from proteotoxic stresses by potentiating stress-induced HSF1 transcriptional activity. Nat. Commun. 6, 6580 (2015).
Hung, Y.H., Chen, L.M., Yang, J.Y. & Yang, W.Y. Spatiotemporally controlled induction of autophagy-mediated lysosome turnover. Nat. Commun. 4, 2111 (2013).
Bejarano, E. et al. Connexins modulate autophagosome biogenesis. Nat. Cell Biol. 16, 401–414 (2014).
Takeuchi, T. et al. Intercellular chaperone transmission via exosomes contributes to maintenance of protein homeostasis at the organismal level. Proc. Natl. Acad. Sci. USA 112, E2497–E2506 (2015).
Lo Cicero, A., Stahl, P.D. & Raposo, G. Extracellular vesicles shuffling intercellular messages: for good or for bad. Curr. Opin. Cell Biol. 35, 69–77 (2015).
Cannizzo, E.S. et al. Age-related oxidative stress compromises endosomal proteostasis. Cell Rep. 2, 136–149 (2012).
Goetzl, E.J. et al. Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neurology 85, 40–47 (2015).
Astanina, K., Koch, M., Jungst, C., Zumbusch, A. & Kiemer, A.K. Lipid droplets as a novel cargo of tunnelling nanotubes in endothelial cells. Sci. Rep. 5, 11453 (2015).
Burtey, A. et al. Intercellular transfer of transferrin receptor by a contact-, Rab8-dependent mechanism involving tunneling nanotubes. FASEB J. 29, 4695–4712 (2015).
Wang, X. & Gerdes, H.H. Transfer of mitochondria via tunneling nanotubes rescues apoptotic PC12 cells. Cell Death Differ. 22, 1181–1191 (2015).
Wang, X. et al. Rescue of brain function using tunneling nanotubes between neural stem cells and brain microvascular endothelial cells. Mol. Neurobiol. doi:10.1007/s12035-015-9225-z (2015).
Agosta, F., Weiler, M. & Filippi, M. Propagation of pathology through brain networks in neurodegenerative diseases: from molecules to clinical phenotypes. CNS Neurosci. Ther. 21, 754–767 (2015).
Russo, I., Bubacco, L. & Greggio, E. Exosomes-associated neurodegeneration and progression of Parkinson′s disease. Am. J. Neurodegener. Dis. 1, 217–225 (2012).
Prusiner, S.B. Biology and genetics of prions causing neurodegeneration. Annu. Rev. Genet. 47, 601–623 (2013).
Gousset, K. et al. Prions hijack tunnelling nanotubes for intercellular spread. Nat. Cell Biol. 11, 328–336 (2009).
Malkus, K.A. & Ischiropoulos, H. Regional deficiencies in chaperone-mediated autophagy underlie alpha-synuclein aggregation and neurodegeneration. Neurobiol. Dis. 46, 732–744 (2012).
Liu, Y., Zhang, X., Chen, W., Tan, Y.L. & Kelly, J.W. Fluorescence turn-on folding sensor to monitor proteome stress in live cells. J. Am. Chem. Soc. 137, 11303–11311 (2015).
Arrasate, M. & Finkbeiner, S. Automated microscope system for determining factors that predict neuronal fate. Proc. Natl. Acad. Sci. USA 102, 3840–3845 (2005).
van Oosten-Hawle, P., Porter, R.S. & Morimoto, R.I. Regulation of organismal proteostasis by transcellular chaperone signaling. Cell 153, 1366–1378 (2013).
Taylor, R.C. & Dillin, A. XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. Cell 153, 1435–1447 (2013).
Williams, K.W. et al. Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab. 20, 471–482 (2014).
Genereux, J.C. et al. Unfolded protein response-induced ERdj3 secretion links ER stress to extracellular proteostasis. EMBO J. 34, 4–19 (2015).
Conboy, M.J., Conboy, I.M. & Rando, T.A. Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity. Aging Cell 12, 525–530 (2013).
Katsimpardi, L. et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344, 630–634 (2014).
de Cabo, R. et al. Serum from calorie-restricted animals delays senescence and extends the lifespan of normal human fibroblasts in vitro. Aging (Albany, NY) 7, 152–166 (2015).
Pratt, W.B., Gestwicki, J.E., Osawa, Y. & Lieberman, A.P. Targeting Hsp90/Hsp70-based protein quality control for treatment of adult onset neurodegenerative diseases. Annu. Rev. Pharmacol. Toxicol. 55, 353–371 (2015).
Walker, G.A. & Lithgow, G.J. Lifespan extension in C. elegans by a molecular chaperone dependent upon insulin-like signals. Aging Cell 2, 131–139 (2003).
Steinkraus, K.A. et al. Dietary restriction suppresses proteotoxicity and enhances longevity by an hsf-1-dependent mechanism in Caenorhabditis elegans. Aging Cell 7, 394–404 (2008).
Chavous, D.A., Jackson, F.R. & O'Connor, C.M. Extension of the Drosophila lifespan by overexpression of a protein repair methyltransferase. Proc. Natl. Acad. Sci. USA 98, 14814–14818 (2001).
Ruan, H. et al. High-quality life extension by the enzyme peptide methionine sulfoxide reductase. Proc. Natl. Acad. Sci. USA 99, 2748–2753 (2002).
Kruegel, U. et al. Elevated proteasome capacity extends replicative lifespan in Saccharomyces cerevisiae. PLoS Genet. 7, e1002253 (2011).
Vilchez, D. et al. RPN-6 determines C. elegans longevity under proteotoxic stress conditions. Nature 489, 263–268 (2012).
Depuydt, G. et al. Reduced insulin/insulin-like growth factor-1 signaling and dietary restriction inhibit translation but preserve muscle mass in Caenorhabditis elegans. Mol. Cell. Proteomics 12, 3624–3639 (2013).
Demontis, F. & Perrimon, N. FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell 143, 813–825 (2010).
Tonoki, A. et al. Genetic evidence linking age-dependent attenuation of the 26S proteasome with the aging process. Mol. Cell. Biol. 29, 1095–1106 (2009).
Crowe, E., Sell, C., Thomas, J.D., Johannes, G.J. & Torres, C. Activation of proteasome by insulin-like growth factor-I may enhance clearance of oxidized proteins in the brain. Mech. Ageing Dev. 130, 793–800 (2009).
Meléndez, A. et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301, 1387–1391 (2003).
Jia, K. & Levine, B. Autophagy is required for dietary restriction-mediated life span extension in C. elegans. Autophagy 3, 597–599 (2007).
Morselli, E. et al. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis. 1, e10 (2010).
Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314 (2009).
Simonsen, A. et al. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy 4, 176–184 (2008).
Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010).
Labunskyy, V.M. et al. Lifespan extension conferred by endoplasmic reticulum secretory pathway deficiency requires induction of the unfolded protein response. PLoS Genet. 10, e1004019 (2014).
Barros, M.H., Bandy, B., Tahara, E.B. & Kowaltowski, A.J. Higher respiratory activity decreases mitochondrial reactive oxygen release and increases life span in Saccharomyces cerevisiae. J. Biol. Chem. 279, 49883–49888 (2004).
McCormick, M.A. et al. A comprehensive analysis of replicative lifespan in 4,698 single-gene deletion strains uncovers conserved mechanisms of aging. Cell Metab. 22, 895–906 (2015).
Henis-Korenblit, S. et al. Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity. Proc. Natl. Acad. Sci. USA 107, 9730–9735 (2010).
Shore, D.E., Carr, C.E. & Ruvkun, G. Induction of cytoprotective pathways is central to the extension of lifespan conferred by multiple longevity pathways. PLoS Genet. 8, e1002792 (2012).
Chen, D., Thomas, E.L. & Kapahi, P. HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in Caenorhabditis elegans. PLoS Genet. 5, e1000486 (2009).
Zid, B.M. et al. 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila. Cell 139, 149–160 (2009).
Kim, H.J., Morrow, G., Westwood, J.T., Michaud, S. & Tanguay, R.M. Gene expression profiling implicates OXPHOS complexes in lifespan extension of flies over-expressing a small mitochondrial chaperone, Hsp22. Exp. Gerontol. 45, 611–620 (2010).
Owusu-Ansah, E., Song, W. & Perrimon, N. Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 155, 699–712 (2013).
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Kaushik, S., Cuervo, A. Proteostasis and aging. Nat Med 21, 1406–1415 (2015). https://doi.org/10.1038/nm.4001
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DOI: https://doi.org/10.1038/nm.4001
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