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Stress Responses pp 215–234Cite as

Stress Responses During Ageing: Molecular Pathways Regulating Protein Homeostasis

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Part of the book series: Methods in Molecular Biology ((MIMB,volume 1292))

Abstract

The ageing process is characterized by deterioration of physiological function accompanied by frailty and ageing-associated diseases. The most broadly and well-studied pathways influencing ageing are the insulin/insulin-like growth factor 1 signaling pathway and the dietary restriction pathway. Recent studies in diverse organisms have also delineated emerging pathways, which collectively or independently contribute to ageing. Among them the proteostatic-stress-response networks, inextricably affect normal ageing by maintaining or restoring protein homeostasis to preserve proper cellular and organismal function. In this chapter, we survey the involvement of heat stress and endoplasmic reticulum stress responses in the regulation of longevity, placing emphasis on the cross talk between different response mechanisms and their systemic effects. We further discuss novel insights relevant to the molecular pathways mediating these stress responses that may facilitate the development of innovative interventions targeting age-related pathologies such as diabetes, cancer, cardiovascular and neurodegenerative diseases.

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References

  1. Kourtis N, Tavernarakis N (2011) Cellular stress response pathways and ageing: intricate molecular relationships. EMBO J 30:2520–2531

    PubMed Central  CAS  PubMed  Google Scholar 

  2. Salminen A, Kaarniranta K (2010) ER stress and hormetic regulation of the aging process. Ageing Res Rev 9:211–217

    CAS  PubMed  Google Scholar 

  3. Tower J (2009) Hsps and aging. Trends Endocrinol Metab 20:216–222

    CAS  PubMed  Google Scholar 

  4. Balch WE, Morimoto RI, Dillin A, Kelly JW (2008) Adapting proteostasis for disease intervention. Science 319:916–919

    CAS  PubMed  Google Scholar 

  5. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217

    PubMed Central  CAS  PubMed  Google Scholar 

  6. Haynes CM, Ron D (2010) The mitochondrial UPR—protecting organelle protein homeostasis. J Cell Sci 123:3849–3855

    CAS  PubMed  Google Scholar 

  7. Bartoszewska M, Williams C, Kikhney A, Opalinski L, van Roermund CW, de Boer R, Veenhuis M, van der Klei IJ (2012) Peroxisomal proteostasis involves a Lon family protein that functions as protease and chaperone. J Biol Chem 287:27380–27395

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Morimoto RI (2011) The heat shock response: systems biology of proteotoxic stress in aging and disease. Cold Spring Harb Symp Quant Biol 76:91–99

    CAS  PubMed  Google Scholar 

  9. Koga H, Kaushik S, Cuervo AM (2011) Protein homeostasis and aging: The importance of exquisite quality control. Ageing Res Rev 10:205–215

    PubMed Central  CAS  PubMed  Google Scholar 

  10. Akerfelt M, Morimoto RI, Sistonen L (2010) Heat shock factors: integrators of cell stress, development and lifespan. Nat Rev Mol Cell Biol 11:545–555

    PubMed Central  CAS  PubMed  Google Scholar 

  11. Wu C (1995) Heat shock transcription factors: structure and regulation. Annu Rev Cell Dev Biol 11:441–469

    CAS  PubMed  Google Scholar 

  12. Bu L, Jin Y, Shi Y, Chu R, Ban A, Eiberg H, Andres L, Jiang H, Zheng G, Qian M, Cui B, Xia Y, Liu J, Hu L, Zhao G, Hayden MR, Kong X (2002) Mutant DNA-binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract. Nat Genet 31:276–278

    CAS  PubMed  Google Scholar 

  13. Fujimoto M, Izu H, Seki K, Fukuda K, Nishida T, Yamada S, Kato K, Yonemura S, Inouye S, Nakai A (2004) HSF4 is required for normal cell growth and differentiation during mouse lens development. EMBO J 23:4297–4306

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Kallio M, Chang Y, Manuel M, Alastalo TP, Rallu M, Gitton Y, Pirkkala L, Loones MT, Paslaru L, Larney S, Hiard S, Morange M, Sistonen L, Mezger V (2002) Brain abnormalities, defective meiotic chromosome synapsis and female subfertility in HSF2 null mice. EMBO J 21:2591–2601

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Morimoto RI (2008) Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev 22:1427–1438

    PubMed Central  CAS  PubMed  Google Scholar 

  16. Sistonen L, Sarge KD, Phillips B, Abravaya K, Morimoto RI (1992) Activation of heat shock factor 2 during hemin-induced differentiation of human erythroleukemia cells. Mol Cell Biol 12:4104–4111

    PubMed Central  CAS  PubMed  Google Scholar 

  17. Zou J, Guo Y, Guettouche T, Smith DF, Voellmy R (1998) Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 94:471–480

    CAS  PubMed  Google Scholar 

  18. Sorger PK, Nelson HC (1989) Trimerization of a yeast transcriptional activator via a coiled-coil motif. Cell 59:807–813

    CAS  PubMed  Google Scholar 

  19. Cotto J, Fox S, Morimoto R (1997) HSF1 granules: a novel stress-induced nuclear compartment of human cells. J Cell Sci 110(Pt 23):2925–2934

    CAS  PubMed  Google Scholar 

  20. Guettouche T, Boellmann F, Lane WS, Voellmy R (2005) Analysis of phosphorylation of human heat shock factor 1 in cells experiencing a stress. BMC Biochem 6:4

    PubMed Central  PubMed  Google Scholar 

  21. Holmberg CI, Hietakangas V, Mikhailov A, Rantanen JO, Kallio M, Meinander A, Hellman J, Morrice N, MacKintosh C, Morimoto RI, Eriksson JE, Sistonen L (2001) Phosphorylation of serine 230 promotes inducible transcriptional activity of heat shock factor 1. EMBO J 20:3800–3810

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Kline MP, Morimoto RI (1997) Repression of the heat shock factor 1 transcriptional activation domain is modulated by constitutive phosphorylation. Mol Cell Biol 17:2107–2115

    PubMed Central  CAS  PubMed  Google Scholar 

  23. Knauf U, Newton EM, Kyriakis J, Kingston RE (1996) Repression of human heat shock factor 1 activity at control temperature by phosphorylation. Genes Dev 10:2782–2793

    CAS  PubMed  Google Scholar 

  24. Sorger PK, Pelham HR (1988) Yeast heat shock factor is an essential DNA-binding protein that exhibits temperature-dependent phosphorylation. Cell 54:855–864

    CAS  PubMed  Google Scholar 

  25. Anckar J, Hietakangas V, Denessiouk K, Thiele DJ, Johnson MS, Sistonen L (2006) Inhibition of DNA binding by differential sumoylation of heat shock factors. Mol Cell Biol 26:955–964

    PubMed Central  CAS  PubMed  Google Scholar 

  26. Hietakangas V, Ahlskog JK, Jakobsson AM, Hellesuo M, Sahlberg NM, Holmberg CI, Mikhailov A, Palvimo JJ, Pirkkala L, Sistonen L (2003) Phosphorylation of serine 303 is a prerequisite for the stress-inducible SUMO modification of heat shock factor 1. Mol Cell Biol 23:2953–2968

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Westerheide SD, Anckar J, Stevens SM Jr, Sistonen L, Morimoto RI (2009) Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science 323:1063–1066

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Raynes R, Leckey BD Jr, Nguyen K, Westerheide SD (2012) Heat shock and caloric restriction have a synergistic effect on the heat shock response in a sir2.1-dependent manner in Caenorhabditis elegans. J Biol Chem 287:29045–29053

    PubMed Central  CAS  PubMed  Google Scholar 

  29. Shi Y, Mosser DD, Morimoto RI (1998) Molecular chaperones as HSF1-specific transcriptional repressors. Genes Dev 12:654–666

    PubMed Central  CAS  PubMed  Google Scholar 

  30. Raynes R, Pombier KM, Nguyen K, Brunquell J, Mendez JE, Westerheide SD (2013) The SIRT1 modulators AROS and DBC1 regulate HSF1 activity and the heat shock response. PLoS One 8:e54364

    PubMed Central  CAS  PubMed  Google Scholar 

  31. Ben-Zvi A, Miller EA, Morimoto RI (2009) Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging. Proc Natl Acad Sci U S A 106:14914–14919

    PubMed Central  CAS  PubMed  Google Scholar 

  32. Shemesh N, Shai N, Ben-Zvi A (2013) Germline stem cell arrest inhibits the collapse of somatic proteostasis early in Caenorhabditis elegans adulthood. Aging Cell 12:814–822

    CAS  PubMed  Google Scholar 

  33. Angeli S, Klang I, Sivapatham R, Mark K, Zucker D, Bhaumik D, Lithgow GJ, Andersen JK (2013) A DNA synthesis inhibitor is protective against proteotoxic stressors via modulation of fertility pathways in Caenorhabditis elegans. Aging (Albany NY) 5:759–769

    CAS  Google Scholar 

  34. Morrow G, Samson M, Michaud S, Tanguay RM (2004) Overexpression of the small mitochondrial Hsp22 extends Drosophila life span and increases resistance to oxidative stress. FASEB J 18:598–599

    CAS  PubMed  Google Scholar 

  35. Walker GA, Lithgow GJ (2003) Lifespan extension in C. elegans by a molecular chaperone dependent upon insulin-like signals. Aging Cell 2:131–139

    CAS  PubMed  Google Scholar 

  36. Swindell WR, Masternak MM, Kopchick JJ, Conover CA, Bartke A, Miller RA (2009) Endocrine regulation of heat shock protein mRNA levels in long-lived dwarf mice. Mech Ageing Dev 130:393–400

    PubMed Central  CAS  PubMed  Google Scholar 

  37. Min JN, Whaley RA, Sharpless NE, Lockyer P, Portbury AL, Patterson C (2008) CHIP deficiency decreases longevity, with accelerated aging phenotypes accompanied by altered protein quality control. Mol Cell Biol 28:4018–4025

    PubMed Central  CAS  PubMed  Google Scholar 

  38. Hsu AL, Murphy CT, Kenyon C (2003) Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300:1142–1145

    CAS  PubMed  Google Scholar 

  39. Morley JF, Morimoto RI (2004) Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol Biol Cell 15:657–664

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Chiang WC, Ching TT, Lee HC, Mousigian C, Hsu AL (2012) HSF-1 regulators DDL-1/2 link insulin-like signaling to heat-shock responses and modulation of longevity. Cell 148:322–334

    PubMed Central  CAS  PubMed  Google Scholar 

  41. Maman M, Carvalhal Marques F, Volovik Y, Dubnikov T, Bejerano-Sagie M, Cohen E (2013) A neuronal GPCR is critical for the induction of the heat shock response in the nematode C. elegans. J Neurosci 33:6102–6111

    CAS  PubMed  Google Scholar 

  42. Shinkawa T, Tan K, Fujimoto M, Hayashida N, Yamamoto K, Takaki E, Takii R, Prakasam R, Inouye S, Mezger V, Nakai A (2011) Heat shock factor 2 is required for maintaining proteostasis against febrile-range thermal stress and polyglutamine aggregation. Mol Biol Cell 22:3571–3583

    PubMed Central  CAS  PubMed  Google Scholar 

  43. Marcuccilli CJ, Mathur SK, Morimoto RI, Miller RJ (1996) Regulatory differences in the stress response of hippocampal neurons and glial cells after heat shock. J Neurosci 16:478–485

    CAS  PubMed  Google Scholar 

  44. Vihervaara A, Sergelius C, Vasara J, Blom MA, Elsing AN, Roos-Mattjus P, Sistonen L (2013) Transcriptional response to stress in the dynamic chromatin environment of cycling and mitotic cells. Proc Natl Acad Sci U S A 110:E3388–E3397

    PubMed Central  CAS  PubMed  Google Scholar 

  45. Gandhapudi SK, Murapa P, Threlkeld ZD, Ward M, Sarge KD, Snow C, Woodward JG (2013) Heat shock transcription factor 1 is activated as a consequence of lymphocyte activation and regulates a major proteostasis network in T cells critical for cell division during stress. J Immunol 191:4068–4079

    CAS  PubMed  Google Scholar 

  46. Anckar J, Sistonen L (2011) Regulation of HSF1 function in the heat stress response: implications in aging and disease. Annu Rev Biochem 80:1089–1115

    CAS  PubMed  Google Scholar 

  47. Shamovsky I, Ivannikov M, Kandel ES, Gershon D, Nudler E (2006) RNA-mediated response to heat shock in mammalian cells. Nature 440:556–560

    CAS  PubMed  Google Scholar 

  48. Kugel JF, Goodrich JA (2006) Beating the heat: a translation factor and an RNA mobilize the heat shock transcription factor HSF1. Mol Cell 22:153–154

    CAS  PubMed  Google Scholar 

  49. Ahn SG, Thiele DJ (2003) Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stress. Genes Dev 17:516–528

    PubMed Central  CAS  PubMed  Google Scholar 

  50. Lu M, Lee YJ, Park SM, Kang HS, Kang SW, Kim S, Park JS (2009) Aromatic-participant interactions are essential for disulfide-bond-based trimerization in human heat shock transcription factor 1. Biochemistry 48:3795–3797

    CAS  PubMed  Google Scholar 

  51. Prahlad V, Cornelius T, Morimoto RI (2008) Regulation of the cellular heat shock response in Caenorhabditis elegans by thermosensory neurons. Science 320:811–814

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Gallo GJ, Prentice H, Kingston RE (1993) Heat shock factor is required for growth at normal temperatures in the fission yeast Schizosaccharomyces pombe. Mol Cell Biol 13:749–761

    PubMed Central  CAS  PubMed  Google Scholar 

  53. Jedlicka P, Mortin MA, Wu C (1997) Multiple functions of Drosophila heat shock transcription factor in vivo. EMBO J 16:2452–2462

    PubMed Central  CAS  PubMed  Google Scholar 

  54. Christians E, Davis AA, Thomas SD, Benjamin IJ (2000) Maternal effect of Hsf1 on reproductive success. Nature 407:693–694

    CAS  PubMed  Google Scholar 

  55. Inouye S, Izu H, Takaki E, Suzuki H, Shirai M, Yokota Y, Ichikawa H, Fujimoto M, Nakai A (2004) Impaired IgG production in mice deficient for heat shock transcription factor 1. J Biol Chem 279:38701–38709

    CAS  PubMed  Google Scholar 

  56. Takii R, Inouye S, Fujimoto M, Nakamura T, Shinkawa T, Prakasam R, Tan K, Hayashida N, Ichikawa H, Hai T, Nakai A (2010) Heat shock transcription factor 1 inhibits expression of IL-6 through activating transcription factor 3. J Immunol 184:1041–1048

    CAS  PubMed  Google Scholar 

  57. Barna J, Princz A, Kosztelnik M, Hargitai B, Takacs-Vellai K, Vellai T (2012) Heat shock factor-1 intertwines insulin/IGF-1, TGF-beta and cGMP signaling to control development and aging. BMC Dev Biol 12:32

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Dai C, Whitesell L, Rogers AB, Lindquist S (2007) Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130:1005–1018

    PubMed Central  CAS  PubMed  Google Scholar 

  59. Min JN, Huang L, Zimonjic DB, Moskophidis D, Mivechi NF (2007) Selective suppression of lymphomas by functional loss of Hsf1 in a p53-deficient mouse model for spontaneous tumors. Oncogene 26:5086–5097

    CAS  PubMed  Google Scholar 

  60. Kim EH, Lee YJ, Bae S, Lee JS, Kim J, Lee YS (2009) Heat shock factor 1-mediated aneuploidy requires a defective function of p53. Cancer Res 69:9404–9412

    CAS  PubMed  Google Scholar 

  61. Whitesell L, Lindquist S (2009) Inhibiting the transcription factor HSF1 as an anticancer strategy. Expert Opin Ther Targets 13:469–478

    CAS  PubMed  Google Scholar 

  62. Travers KJ, Patil CK, Wodicka L, Lockhart DJ, Weissman JS, Walter P (2000) Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101:249–258

    CAS  PubMed  Google Scholar 

  63. Schroder M (2008) Endoplasmic reticulum stress responses. Cell Mol Life Sci 65:862–894

    CAS  PubMed  Google Scholar 

  64. Malhotra JD, Kaufman RJ (2007) Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal 9:2277–2293

    CAS  PubMed  Google Scholar 

  65. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529

    CAS  PubMed  Google Scholar 

  66. Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5:897–904

    CAS  PubMed  Google Scholar 

  67. Chen X, Shen J, Prywes R (2002) The luminal domain of ATF6 senses endoplasmic reticulum (ER) stress and causes translocation of ATF6 from the ER to the Golgi. J Biol Chem 277:13045–13052

    CAS  PubMed  Google Scholar 

  68. Shen J, Chen X, Hendershot L, Prywes R (2002) ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell 3:99–111

    CAS  PubMed  Google Scholar 

  69. Han D, Lerner AG, Vande Walle L, Upton JP, Xu W, Hagen A, Backes BJ, Oakes SA, Papa FR (2009) IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138:562–575

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Szegezdi E, Logue SE, Gorman AM, Samali A (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7:880–885

    PubMed Central  CAS  PubMed  Google Scholar 

  71. Fribley A, Zhang K, Kaufman RJ (2009) Regulation of apoptosis by the unfolded protein response. Methods Mol Biol 559:191–204

    PubMed Central  CAS  PubMed  Google Scholar 

  72. Samali A, Fitzgerald U, Deegan S, Gupta S (2010) Methods for monitoring endoplasmic reticulum stress and the unfolded protein response. Int J Cell Biol 2010:830307

    PubMed Central  PubMed  Google Scholar 

  73. Iwawaki T, Akai R, Kohno K, Miura M (2004) A transgenic mouse model for monitoring endoplasmic reticulum stress. Nat Med 10:98–102

    CAS  PubMed  Google Scholar 

  74. Merksamer PI, Trusina A, Papa FR (2008) Real-time redox measurements during endoplasmic reticulum stress reveal interlinked protein folding functions. Cell 135:933–947

    PubMed Central  CAS  PubMed  Google Scholar 

  75. Thorp E, Iwawaki T, Miura M, Tabas I (2011) A reporter for tracking the UPR in vivo reveals patterns of temporal and cellular stress during atherosclerotic progression. J Lipid Res 52:1033–1038

    PubMed Central  CAS  PubMed  Google Scholar 

  76. Hiramatsu N, Kasai A, Hayakawa K, Yao J, Kitamura M (2006) Real-time detection and continuous monitoring of ER stress in vitro and in vivo by ES-TRAP: evidence for systemic, transient ER stress during endotoxemia. Nucleic Acids Res 34:e93

    PubMed Central  PubMed  Google Scholar 

  77. Chitnis N, Pytel D, Diehl JA (2013) UPR-inducible miRNAs contribute to stressful situations. Trends Biochem Sci 38:447–452

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Bartoszewska S, Kochan K, Madanecki P, Piotrowski A, Ochocka R, Collawn JF, Bartoszewski R (2013) Regulation of the unfolded protein response by microRNAs. Cell Mol Biol Lett 18(4):555–578

    CAS  PubMed  Google Scholar 

  79. Chitnis NS, Pytel D, Bobrovnikova-Marjon E, Pant D, Zheng H, Maas NL, Frederick B, Kushner JA, Chodosh LA, Koumenis C, Fuchs SY, Diehl JA (2012) miR-211 is a prosurvival microRNA that regulates chop expression in a PERK-dependent manner. Mol Cell 48:353–364

    PubMed Central  CAS  PubMed  Google Scholar 

  80. Byrd AE, Aragon IV, Brewer JW (2012) MicroRNA-30c-2* limits expression of proadaptive factor XBP1 in the unfolded protein response. J Cell Biol 196:689–698

    PubMed Central  CAS  PubMed  Google Scholar 

  81. Upton JP, Wang L, Han D, Wang ES, Huskey NE, Lim L, Truitt M, McManus MT, Ruggero D, Goga A, Papa FR, Oakes SA (2012) IRE1alpha cleaves select microRNAs during ER stress to derepress translation of proapoptotic caspase-2. Science 338:818–822

    PubMed Central  CAS  PubMed  Google Scholar 

  82. Cawley K, Logue SE, Gorman AM, Zeng Q, Patterson J, Gupta S, Samali A (2013) Disruption of microRNA biogenesis confers resistance to ER stress-induced cell death upstream of the mitochondrion. PLoS One 8:e73870

    PubMed Central  CAS  PubMed  Google Scholar 

  83. Naidoo N, Ferber M, Master M, Zhu Y, Pack AI (2008) Aging impairs the unfolded protein response to sleep deprivation and leads to proapoptotic signaling. J Neurosci 28:6539–6548

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Hussain SG, Ramaiah KV (2007) Reduced eIF2alpha phosphorylation and increased proapoptotic proteins in aging. Biochem Biophys Res Commun 355:365–370

    CAS  PubMed  Google Scholar 

  85. Nuss JE, Choksi KB, DeFord JH, Papaconstantinou J (2008) Decreased enzyme activities of chaperones PDI and BiP in aged mouse livers. Biochem Biophys Res Commun 365:355–361

    PubMed Central  CAS  PubMed  Google Scholar 

  86. Paz Gavilan M, Vela J, Castano A, Ramos B, del Rio JC, Vitorica J, Ruano D (2006) Cellular environment facilitates protein accumulation in aged rat hippocampus. Neurobiol Aging 27:973–982

    CAS  PubMed  Google Scholar 

  87. Engin F, Yermalovich A, Ngyuen T, Hummasti S, Fu W, Eizirik DL, Mathis D, Hotamisligil GS (2013) Restoration of the unfolded protein response in pancreatic beta cells protects mice against type 1 diabetes. Sci Transl Med 5: 211ra156

    Google Scholar 

  88. Haskins KA, Russell JF, Gaddis N, Dressman HK, Aballay A (2008) Unfolded protein response genes regulated by CED-1 are required for Caenorhabditis elegans innate immunity. Dev Cell 15:87–97

    PubMed Central  CAS  PubMed  Google Scholar 

  89. Sun J, Singh V, Kajino-Sakamoto R, Aballay A (2011) Neuronal GPCR controls innate immunity by regulating noncanonical unfolded protein response genes. Science 332:729–732

    PubMed Central  CAS  PubMed  Google Scholar 

  90. Menu P, Mayor A, Zhou R, Tardivel A, Ichijo H, Mori K, Tschopp J (2012) ER stress activates the NLRP3 inflammasome via an UPR-independent pathway. Cell Death Dis 3:e261

    PubMed Central  CAS  PubMed  Google Scholar 

  91. Lu M, Sun XL, Qiao C, Liu Y, Ding JH, Hu G (2014) Uncoupling protein 2 deficiency aggravates astrocytic endoplasmic reticulum stress and nod-like receptor protein 3 inflammasome activation. Neurobiol Aging 35:421–430

    CAS  PubMed  Google Scholar 

  92. Lerner AG, Upton JP, Praveen PV, Ghosh R, Nakagawa Y, Igbaria A, Shen S, Nguyen V, Backes BJ, Heiman M, Heintz N, Greengard P, Hui S, Tang Q, Trusina A, Oakes SA, Papa FR (2012) IRE1alpha induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab 16:250–264

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Oslowski CM, Hara T, O’Sullivan-Murphy B, Kanekura K, Lu S, Hara M, Ishigaki S, Zhu LJ, Hayashi E, Hui ST, Greiner D, Kaufman RJ, Bortell R, Urano F (2012) Thioredoxin-interacting protein mediates ER stress-induced beta cell death through initiation of the inflammasome. Cell Metab 16:265–273

    PubMed Central  CAS  PubMed  Google Scholar 

  94. Bishop NA, Guarente L (2007) Two neurons mediate diet-restriction-induced longevity in C. elegans. Nature 447:545–549

    CAS  PubMed  Google Scholar 

  95. Broughton SJ, Piper MD, Ikeya T, Bass TM, Jacobson J, Driege Y, Martinez P, Hafen E, Withers DJ, Leevers SJ, Partridge L (2005) Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. Proc Natl Acad Sci U S A 102:3105–3110

    PubMed Central  CAS  PubMed  Google Scholar 

  96. Hsin H, Kenyon C (1999) Signals from the reproductive system regulate the lifespan of C. elegans. Nature 399:362–366

    CAS  PubMed  Google Scholar 

  97. Ermolaeva MA, Segref A, Dakhovnik A, Ou HL, Schneider JI, Utermohlen O, Hoppe T, Schumacher B (2013) DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature 501:416–420

    PubMed Central  CAS  PubMed  Google Scholar 

  98. Lionaki E, Tavernarakis N (2013) Oxidative stress and mitochondrial protein quality control in aging. J Proteome 92:181–194

    CAS  Google Scholar 

  99. Raffaello A, Rizzuto R (2011) Mitochondrial longevity pathways. Biochim Biophys Acta 1813:260–268

    CAS  PubMed  Google Scholar 

  100. Durieux J, Wolff S, Dillin A (2011) The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 144:79–91

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Taylor RC, Dillin A (2013) XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. Cell 153:1435–1447

    CAS  PubMed  Google Scholar 

  102. Sun J, Liu Y, Aballay A (2012) Organismal regulation of XBP-1-mediated unfolded protein response during development and immune activation. EMBO Rep 13:855–860

    PubMed Central  CAS  PubMed  Google Scholar 

  103. Guisbert E, Czyz DM, Richter K, McMullen PD, Morimoto RI (2013) Identification of a tissue-selective heat shock response regulatory network. PLoS Genet 9:e1003466

    PubMed Central  CAS  PubMed  Google Scholar 

  104. van Oosten-Hawle P, Porter RS, Morimoto RI (2013) Regulation of organismal proteostasis by transcellular chaperone signaling. Cell 153:1366–1378

    PubMed Central  PubMed  Google Scholar 

  105. Prahlad V, Morimoto RI (2011) Neuronal circuitry regulates the response of Caenorhabditis elegans to misfolded proteins. Proc Natl Acad Sci U S A 108:14204–14209

    PubMed Central  CAS  PubMed  Google Scholar 

  106. Schneeberger M, Dietrich MO, Sebastian D, Imbernon M, Castano C, Garcia A, Esteban Y, Gonzalez-Franquesa A, Rodriguez IC, Bortolozzi A, Garcia-Roves PM, Gomis R, Nogueiras R, Horvath TL, Zorzano A, Claret M (2013) Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell 155:172–187

    CAS  PubMed  Google Scholar 

  107. Ben-Gedalya T, Cohen E (2012) Quality control compartments coming of age. Traffic 13:635–642

    CAS  PubMed  Google Scholar 

  108. Kregel KC (2002) Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. J Appl Physiol (1985) 92:2177–2186

    CAS  Google Scholar 

  109. Fargnoli J, Kunisada T, Fornace AJ Jr, Schneider EL, Holbrook NJ (1990) Decreased expression of heat shock protein 70 mRNA and protein after heat treatment in cells of aged rats. Proc Natl Acad Sci U S A 87:846–850

    PubMed Central  CAS  PubMed  Google Scholar 

  110. Liu AY, Lin Z, Choi HS, Sorhage F, Li B (1989) Attenuated induction of heat shock gene expression in aging diploid fibroblasts. J Biol Chem 264:12037–12045

    CAS  PubMed  Google Scholar 

  111. Blake MJ, Fargnoli J, Gershon D, Holbrook NJ (1991) Concomitant decline in heat-induced hyperthermia and HSP70 mRNA expression in aged rats. Am J Physiol 260:R663–R667

    CAS  PubMed  Google Scholar 

  112. Hall DM, Xu L, Drake VJ, Oberley LW, Oberley TD, Moseley PL, Kregel KC (2000) Aging reduces adaptive capacity and stress protein expression in the liver after heat stress. J Appl Physiol (1985) 89:749–759

    CAS  Google Scholar 

  113. Kregel KC, Moseley PL, Skidmore R, Gutierrez JA, Guerriero V Jr (1995) HSP70 accumulation in tissues of heat-stressed rats is blunted with advancing age. J Appl Physiol (1985) 79:1673–1678

    CAS  Google Scholar 

  114. Nitta Y, Abe K, Aoki M, Ohno I, Isoyama S (1994) Diminished heat shock protein 70 mRNA induction in aged rat hearts after ischemia. Am J Physiol 267:H1795–H1803

    CAS  PubMed  Google Scholar 

  115. Fawcett TW, Sylvester SL, Sarge KD, Morimoto RI, Holbrook NJ (1994) Effects of neurohormonal stress and aging on the activation of mammalian heat shock factor 1. J Biol Chem 269:32272–32278

    CAS  PubMed  Google Scholar 

  116. Locke M, Tanguay RM (1996) Diminished heat shock response in the aged myocardium. Cell Stress Chaperones 1:251–260

    PubMed Central  CAS  PubMed  Google Scholar 

  117. Hageman J, Rujano MA, van Waarde MA, Kakkar V, Dirks RP, Govorukhina N, Oosterveld-Hut HM, Lubsen NH, Kampinga HH (2010) A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic protein aggregation. Mol Cell 37:355–369

    CAS  PubMed  Google Scholar 

  118. Kazemi-Esfarjani P, Benzer S (2000) Genetic suppression of polyglutamine toxicity in Drosophila. Science 287:1837–1840

    CAS  PubMed  Google Scholar 

  119. Labbadia J, Novoselov SS, Bett JS, Weiss A, Paganetti P, Bates GP, Cheetham ME (2012) Suppression of protein aggregation by chaperone modification of high molecular weight complexes. Brain 135:1180–1196

    PubMed Central  PubMed  Google Scholar 

  120. Chafekar SM, Duennwald ML (2012) Impaired heat shock response in cells expressing full-length polyglutamine-expanded huntingtin. PLoS One 7:e37929

    PubMed Central  CAS  PubMed  Google Scholar 

  121. Riva L, Koeva M, Yildirim F, Pirhaji L, Dinesh D, Mazor T, Duennwald ML, Fraenkel E (2012) Poly-glutamine expanded huntingtin dramatically alters the genome wide binding of HSF1. J Huntingtons Dis 1:33–45

    PubMed Central  PubMed  Google Scholar 

  122. Wang AM, Miyata Y, Klinedinst S, Peng HM, Chua JP, Komiyama T, Li X, Morishima Y, Merry DE, Pratt WB, Osawa Y, Collins CA, Gestwicki JE, Lieberman AP (2013) Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation. Nat Chem Biol 9:112–118

    PubMed Central  CAS  PubMed  Google Scholar 

  123. Calamini B, Silva MC, Madoux F, Hutt DM, Khanna S, Chalfant MA, Allais C, Ouizem S, Saldanha SA, Ferguson J, Mercer BA, Michael C, Tait BD, Garza D, Balch WE, Roush WR, Morimoto RI, Hodder P (2010) ML346: a novel modulator of proteostasis for protein conformational diseases. In: Probe reports from the NIH Molecular Libraries Program. National Center for Biotechnology Information (US), Bethesda, MD

    Google Scholar 

  124. Zhang K, Kaufman RJ (2008) From endoplasmic-reticulum stress to the inflammatory response. Nature 454:455–462

    PubMed Central  CAS  PubMed  Google Scholar 

  125. Hotamisligil GS (2010) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140:900–917

    PubMed Central  CAS  PubMed  Google Scholar 

  126. Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini DD, Ron D (2001) Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell 7:1153–1163

    CAS  PubMed  Google Scholar 

  127. Back SH, Scheuner D, Han J, Song B, Ribick M, Wang J, Gildersleeve RD, Pennathur S, Kaufman RJ (2009) Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells. Cell Metab 10:13–26

    PubMed Central  CAS  PubMed  Google Scholar 

  128. Alavez S, Vantipalli MC, Zucker DJ, Klang IM, Lithgow GJ (2011) Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature 472:226–229

    PubMed Central  CAS  PubMed  Google Scholar 

  129. Schulze A, Harris AL (2012) How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature 491:364–373

    CAS  PubMed  Google Scholar 

  130. Koong AC, Chauhan V, Romero-Ramirez L (2006) Targeting XBP-1 as a novel anti-cancer strategy. Cancer Biol Ther 5:756–759

    CAS  PubMed  Google Scholar 

  131. Ryno LM, Wiseman RL, Kelly JW (2013) Targeting unfolded protein response signaling pathways to ameliorate protein misfolding diseases. Curr Opin Chem Biol 17:346–352

    CAS  PubMed  Google Scholar 

  132. Calamini B, Silva MC, Madoux F, Hutt DM, Khanna S, Chalfant MA, Saldanha SA, Hodder P, Tait BD, Garza D, Balch WE, Morimoto RI (2012) Small-molecule proteostasis regulators for protein conformational diseases. Nat Chem Biol 8:185–196

    CAS  Google Scholar 

  133. Pyrko P, Schonthal AH, Hofman FM, Chen TC, Lee AS (2007) The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Cancer Res 67:9809–9816

    CAS  PubMed  Google Scholar 

  134. Buontempo F, Orsini E, Martins LR, Antunes I, Lonetti A, Chiarini F, Tabellini G, Evangelisti C, Melchionda F, Pession A, Bertaina A, Locatelli F, McCubrey JA, Cappellini A, Barata JT, Martelli AM (2013) Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the unfolded protein response signaling. Leukemia 28(3):543–553

    PubMed  Google Scholar 

  135. Vilchez D, Boyer L, Morantte I, Lutz M, Merkwirth C, Joyce D, Spencer B, Page L, Masliah E, Berggren WT, Gage FH, Dillin A (2012) Increased proteasome activity in human embryonic stem cells is regulated by PSMD11. Nature 489:304–308

    CAS  PubMed  Google Scholar 

  136. Chung CY, Khurana V, Auluck PK, Tardiff DF, Mazzulli JR, Soldner F, Baru V, Lou Y, Freyzon Y, Cho S, Mungenast AE, Muffat J, Mitalipova M, Pluth MD, Jui NT, Schule B, Lippard SJ, Tsai LH, Krainc D, Buchwald SL, Jaenisch R, Lindquist S (2013) Identification and rescue of alpha-synuclein toxicity in Parkinson patient-derived neurons. Science 342:983–987

    PubMed Central  CAS  PubMed  Google Scholar 

  137. Heijmans J, Lidth v, de Jeude JF, Koo BK, Rosekrans SL, Wielenga MC, van de Wetering M, Ferrante M, Lee AS, Onderwater JJ, Paton JC, Paton AW, Mommaas AM, Kodach LL, Hardwick JC, Hommes DW, Clevers H, Muncan V, van den Brink GR (2013) ER stress causes rapid loss of intestinal epithelial stemness through activation of the unfolded protein response. Cell Rep 3:1128–1139

    CAS  PubMed  Google Scholar 

  138. Rouault-Pierre K, Lopez-Onieva L, Foster K, Anjos-Afonso F, Lamrissi-Garcia I, Serrano-Sanchez M, Mitter R, Ivanovic Z, de Verneuil H, Gribben J, Taussig D, Rezvani HR, Mazurier F, Bonnet D (2013) HIF-2alpha protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress. Cell Stem Cell 13:549–563

    CAS  PubMed  Google Scholar 

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Acknowledgements

We apologize to those colleagues whose work could not be referenced directly owing to space limitations. E.K. is supported by the General Secretariat for Research and Technology of the Greek Ministry of Education. A.P. is supported by a European Commission Marie Curie Actions Programme, Initial Training fellowship. Work in the authors’ laboratory is also funded by grants from the European Research Council (ERC) and the European Commission Seventh Framework Programme.

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Authors and Affiliations

  1. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, N. Plastira 100, Vassilika Vouton, 1385, Heraklion, 70013, Crete, Greece

    Emmanouil Kyriakakis, Andrea Princz & Nektarios Tavernarakis

  2. Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion, 70013, Crete, Greece

    Nektarios Tavernarakis

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  1. Emmanouil Kyriakakis
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  2. Andrea Princz
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  3. Nektarios Tavernarakis
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Correspondence to Nektarios Tavernarakis .

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  1. Wentworth Institute of Technology, Boston, Massachusetts, USA

    Christine M. Oslowski

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Kyriakakis, E., Princz, A., Tavernarakis, N. (2015). Stress Responses During Ageing: Molecular Pathways Regulating Protein Homeostasis. In: Oslowski, C. (eds) Stress Responses. Methods in Molecular Biology, vol 1292. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2522-3_16

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  • DOI: https://doi.org/10.1007/978-1-4939-2522-3_16

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-2521-6

  • Online ISBN: 978-1-4939-2522-3

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