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Vol. 55, No. 5, 2009
Issue release date: September 2009
Section title: Experimental Section
Free Access
Gerontology 2009;55:550–558
(DOI:10.1159/000225957)

The Shock of Aging: Molecular Chaperones and the Heat Shock Response in Longevity and Aging – A Mini-Review

Calderwood S.K. · Murshid A. · Prince T.
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass., USA
email Corresponding Author

Abstract

Background: Aging can be thought of as the collision between destructive processes that act on cells and organs over the lifetime and the responses that promote homeostasis, vitality and longevity. However, the precise mechanisms that determine the rates of aging in organisms are not known. Objective: Macromolecules such as proteins are continuously exposed to potential damaging agents that can cause loss of molecular function and depletion of cell populations over the lifetime of essential organs. One of the key homeostatic responses involved in maintaining longevity is the induction of heat shock proteins (HSPs), a conserved reaction to damaged intracellular proteins. We aim to discuss how the interplay between protein damage and its repair or removal from the cell may influence longevity and aging. Methods: We have reviewed experiments carried out in mammalian and non-mammalian organisms on molecular chaperones and the transcription factor (heat shock factor 1, HSF1) responsible for their expression. We have discussed mechanisms through which these molecules are regulated in cells, respond to stimuli that enhance longevity and become impaired during aging. Results: The transcription factor HSF1 initiates the prolific induction of HSP when cells are exposed to protein damage. HSPs are molecular chaperones that protect the proteome by folding denatured polypeptides and promoting the degradation of severely damaged proteins. Activation of HSF1 is coupled functionally to fundamental pathways of longevity and orchestrates the evasion of aging through HSP induction and antagonism of protein aggregation. In addition to mediating protein quality control, some HSPs such as Hsp27 and Hsp70 directly protect cells against damage-induced entry into death pathways. However, the heat shock response declines in potency over the lifetime, and enfeeblement of the response contributes to aging by permitting the emergence of protein aggregation diseases, reduction in cellular vigor and decreased longevity. Conclusions: Molecular chaperones play an important role in the deterrence of protein damage during aging and their expression is required for longevity. Chemical stimulation of HSP synthesis might therefore be a significant strategy in future design of antiaging pharmaceuticals.

© 2009 S. Karger AG, Basel


  

Key Words

  • Heat shock protein
  • Aging
  • Aggregation
  • Molecular chaperone
  • CHIP
  • Ubiquitin
  • Proteasome
  • Heat shock factor 1

References

  1. Westphal CH, Dipp MA, Guarente L: A therapeutic role for sirtuins in diseases of aging? Trends Biochem Sci 2007;32:555–560.
  2. Lindquist S, Craig EA: The heat shock proteins. Annu Rev Genet 1988;22:631–637.
  3. Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G: Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle 2006;5:2592–2601.
  4. Ellis RJ: Protein misassembly: macromolecular crowding and molecular chaperones. Adv Exp Med Biol 2007;594:1–13.
  5. Sherman MY, Goldberg AL: Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron 2001;29:15–32.
  6. Winklhofer KF, Tatzelt J, Haass C: The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases. EMBO J 2008;27:336–349.
  7. Hands S, Sinadinos C, Wyttenbach A: Polyglutamine gene function and dysfunction in the ageing brain. Biochim Biophys Acta 2008;1779:507–521.
  8. Kayani AC, Morton JP, McArdle A: The exercise-induced stress response in skeletal muscle: failure during aging. Appl Physiol Nutr Metab 2008;33:1033–1041.
  9. Gagliano N, Grizzi F, Annoni G: Mechanisms of aging and liver functions. Dig Dis 2007;25:118–123.
  10. Calderwood SK: Molecular Chaperones and the Ubiquitin Proteasome System in Aging. New York, Nova, 2007.
  11. Mayer MP, Bukau B: Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci 2005;62:670–684.
  12. D’Andrea LD, Regan L: TPR proteins: the versatile helix. Trends Biochem Sci 2003;28:655–662.
  13. Hut HM, Kampinga HH, Sibon OC: Hsp70 protects mitotic cells against heat-induced centrosome damage and division abnormalities. Mol Biol Cell 2005;16:3776–3785.
  14. Gray PJ Jr, Prince T, Cheng J, Stevenson MA, Calderwood SK: Targeting the oncogene and kinome chaperone CDC37. Nat Rev Cancer 2008;8:491–495.
  15. Marques C, Guo W, Pereira P, Taylor A, Patterson C, Evans PC, Shang F: The triage of damaged proteins: degradation by the ubiquitin-proteasome pathway or repair by molecular chaperones. FASEB J 2006;20:741–743.
  16. Min JN, Whaley RA, Sharpless NE, Lockyer P, Portbury AL, Patterson C: CHIP deficiency decreases longevity, with accelerated aging phenotypes accompanied by altered protein quality control. Mol Cell Biol 2008;28:4018–4025.
  17. Dice JF: Chaperone-mediated autophagy. Autophagy 2007;3:295–299.
  18. Rujano MA, Bosveld F, Salomons FA, Dijk F, van Waarde MA, van der Want JJ, de Vos RA, Brunt ER, Sibon OC, Kampinga HH: Polarised asymmetric inheritance of accumulated protein damage in higher eukaryotes. PLoS Biol 2006;4:e417.
  19. Boyault C, Zhang Y, Fritah S, Caron C, Gilquin B, Kwon SH, Garrido C, Yao TP, Vourc’h C, Matthias P, Khochbin S: HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates. Genes Dev 2007;21:2172–2181.
  20. Kovacs JJ, Murphy PJ, Gaillard S, Zhao X, Wu JT, Nicchitta CV, Yoshida M, Toft DO, Pratt WB, Yao TP: HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell 2005;18:601–607.
  21. Westerheide SD, Anckar J, Stevens SM Jr, Sistonen L, Morimoto RI: Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science 2009;323:1063–1066.
  22. Hsu AL, Murphy CT, Kenyon C: Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 2003;300:1142–1145.
  23. Steinkraus KA, Smith ED, Davis C, Carr D, Pendergrass WR, Sutphin GL, Kennedy BK, Kaeberlein M: Dietary restriction suppresses proteotoxicity and enhances longevity by an hsf-1-dependent mechanism in Caenorhabditis elegans. Aging Cell 2008;7:394–404.
  24. Kurapati R, Passananti HB, Rose MR, Tower J: Increased hsp22 RNA levels in Drosophila lines genetically selected for increased longevity. J Gerontol A Biol Sci Med Sci 2000;55:B552–559.
  25. Morrow G, Samson M, Michaud S, Tanguay RM: Overexpression of the small mitochondrial Hsp22 extends Drosophila life span and increases resistance to oxidative stress. FASEB J 2004;18:598–599.
  26. Arrigo AP: The cellular ‘networking’ of mammalian Hsp27 and its functions in the control of protein folding, redox state and apoptosis. Adv Exp Med Biol 2007;594:14–26.
  27. Wyttenbach A, Sauvageot O, Carmichael J, Diaz-Latoud C, Arrigo AP, Rubinsztein DC: Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin. Hum Mol Genet 2002;11:1137–1151.
  28. Benndorf R, Welsh MJ: Shocking degeneration. Nat Genet 2004;36:547–548.
  29. Evgrafov OV, Mersiyanova I, Irobi J, Van Den Bosch L, Dierick I, Leung CL, Schagina O, Verpoorten N, Van Impe K, Fedotov V, Dadali E, Auer-Grumbach M, Windpassinger C, Wagner K, Mitrovic Z, Hilton-Jones D, Talbot K, Martin JJ, Vasserman N, Tverskaya S, Polyakov A, Liem RK, Gettemans J, Robberecht W, De Jonghe P, Timmerman V: Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet 2004;36:602–606.
  30. Wu C: Heat shock transcription factors: structure and regulation. Annu Rev Cell Dev Biol 1995;11:441–469.
  31. Kaarniranta K, Oksala N, Karjalainen HM, Suuronen T, Sistonen L, Helminen HJ, Salminen A, Lammi MJ: Neuronal cells show regulatory differences in the hsp70 gene response. Brain Res Mol Brain Res 2002;101:136–140.
  32. Batulan Z, Shinder GA, Minotti S, He BP, Doroudchi MM, Nalbantoglu J, Strong MJ, Durham HD: High threshold for induction of the stress response in motor neurons is associated with failure to activate HSF1. J Neurosci 2003;23:5789–5798.
  33. Khaleque MA, Bharti A, Sawyer D, Gong J, Benjamin IJ, Stevenson MA, Calderwood SK: Induction of heat shock proteins by heregulin β1 leads to protection from apoptosis and anchorage-independent growth. Oncogene 2005;24:6564–6573.
  34. Wang X, Grammatikakis N, Siganou A, Calderwood SK: Regulation of molecular chaperone gene transcription involves the serine phosphorylation, 14-3-3 epsilon binding, and cytoplasmic sequestration of heat shock factor 1. Mol Cell Biol 2003;23:6013–6026.
  35. Shamovsky I, Ivannikov M, Kandel ES, Gershon D, Nudler E: RNA-mediated response to heat shock in mammalian cells. Nature 2006;440:556–560.
  36. Chang R, Wang E: Mouse translation elongation factor eEF1A-2 interacts with Prdx-I to protect cells against apoptotic death induced by oxidative stress. J Cell Biochem 2007;100:267–278.
  37. Chu B, Soncin F, Price BD, Stevenson MA, Calderwood SK: Sequential phosphorylation by mitogen-activated protein kinase and glycogen synthase kinase 3 represses transcriptional activation by heat shock factor-1. J Biol Chem 1996;271:30847–30857.
  38. Bhat RV, Budd Haeberlein SL, Avila J: Glycogen synthase kinase 3: a drug target for CNS therapies. J Neurochem 2004;89:1313–1317.
  39. Takahashi R, Imai Y: Pael receptor, endoplasmic reticulum stress, and Parkinson’s disease. J Neurol 2003;250(suppl 3):III25–III29.
  40. Jana NR, Dikshit P, Goswami A, Kotliarova S, Murata S, Tanaka K, Nukina N: Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes. J Biol Chem 2005;280:11635–11640.

  

Author Contacts

Dr. Stuart K. Calderwood
BIDMC, 99 Brookline Avenue, Room 325E
Boston, MA 02215 (USA)
Tel. +1 617 667 0970, Fax +1 617 975 5240
E-Mail scalderw@bidmc.harvard.edu

  

Article Information

Received: December 11, 2008
Accepted: April 29, 2009
Published online: June 18, 2009
Number of Print Pages : 9
Number of Figures : 4, Number of Tables : 1, Number of References : 40

  

Publication Details

Gerontology (International Journal of Experimental, Clinical, Behavioural and Technological Gerontology)

Vol. 55, No. 5, Year 2009 (Cover Date: September 2009)

Journal Editor: Wick G. (Innsbruck)
ISSN: 0304-324X (Print), eISSN: 1423-0003 (Online)

For additional information: http://www.karger.com/GER


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References

  1. Westphal CH, Dipp MA, Guarente L: A therapeutic role for sirtuins in diseases of aging? Trends Biochem Sci 2007;32:555–560.
  2. Lindquist S, Craig EA: The heat shock proteins. Annu Rev Genet 1988;22:631–637.
  3. Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G: Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle 2006;5:2592–2601.
  4. Ellis RJ: Protein misassembly: macromolecular crowding and molecular chaperones. Adv Exp Med Biol 2007;594:1–13.
  5. Sherman MY, Goldberg AL: Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron 2001;29:15–32.
  6. Winklhofer KF, Tatzelt J, Haass C: The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases. EMBO J 2008;27:336–349.
  7. Hands S, Sinadinos C, Wyttenbach A: Polyglutamine gene function and dysfunction in the ageing brain. Biochim Biophys Acta 2008;1779:507–521.
  8. Kayani AC, Morton JP, McArdle A: The exercise-induced stress response in skeletal muscle: failure during aging. Appl Physiol Nutr Metab 2008;33:1033–1041.
  9. Gagliano N, Grizzi F, Annoni G: Mechanisms of aging and liver functions. Dig Dis 2007;25:118–123.
  10. Calderwood SK: Molecular Chaperones and the Ubiquitin Proteasome System in Aging. New York, Nova, 2007.
  11. Mayer MP, Bukau B: Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci 2005;62:670–684.
  12. D’Andrea LD, Regan L: TPR proteins: the versatile helix. Trends Biochem Sci 2003;28:655–662.
  13. Hut HM, Kampinga HH, Sibon OC: Hsp70 protects mitotic cells against heat-induced centrosome damage and division abnormalities. Mol Biol Cell 2005;16:3776–3785.
  14. Gray PJ Jr, Prince T, Cheng J, Stevenson MA, Calderwood SK: Targeting the oncogene and kinome chaperone CDC37. Nat Rev Cancer 2008;8:491–495.
  15. Marques C, Guo W, Pereira P, Taylor A, Patterson C, Evans PC, Shang F: The triage of damaged proteins: degradation by the ubiquitin-proteasome pathway or repair by molecular chaperones. FASEB J 2006;20:741–743.
  16. Min JN, Whaley RA, Sharpless NE, Lockyer P, Portbury AL, Patterson C: CHIP deficiency decreases longevity, with accelerated aging phenotypes accompanied by altered protein quality control. Mol Cell Biol 2008;28:4018–4025.
  17. Dice JF: Chaperone-mediated autophagy. Autophagy 2007;3:295–299.
  18. Rujano MA, Bosveld F, Salomons FA, Dijk F, van Waarde MA, van der Want JJ, de Vos RA, Brunt ER, Sibon OC, Kampinga HH: Polarised asymmetric inheritance of accumulated protein damage in higher eukaryotes. PLoS Biol 2006;4:e417.
  19. Boyault C, Zhang Y, Fritah S, Caron C, Gilquin B, Kwon SH, Garrido C, Yao TP, Vourc’h C, Matthias P, Khochbin S: HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates. Genes Dev 2007;21:2172–2181.
  20. Kovacs JJ, Murphy PJ, Gaillard S, Zhao X, Wu JT, Nicchitta CV, Yoshida M, Toft DO, Pratt WB, Yao TP: HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell 2005;18:601–607.
  21. Westerheide SD, Anckar J, Stevens SM Jr, Sistonen L, Morimoto RI: Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science 2009;323:1063–1066.
  22. Hsu AL, Murphy CT, Kenyon C: Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 2003;300:1142–1145.
  23. Steinkraus KA, Smith ED, Davis C, Carr D, Pendergrass WR, Sutphin GL, Kennedy BK, Kaeberlein M: Dietary restriction suppresses proteotoxicity and enhances longevity by an hsf-1-dependent mechanism in Caenorhabditis elegans. Aging Cell 2008;7:394–404.
  24. Kurapati R, Passananti HB, Rose MR, Tower J: Increased hsp22 RNA levels in Drosophila lines genetically selected for increased longevity. J Gerontol A Biol Sci Med Sci 2000;55:B552–559.
  25. Morrow G, Samson M, Michaud S, Tanguay RM: Overexpression of the small mitochondrial Hsp22 extends Drosophila life span and increases resistance to oxidative stress. FASEB J 2004;18:598–599.
  26. Arrigo AP: The cellular ‘networking’ of mammalian Hsp27 and its functions in the control of protein folding, redox state and apoptosis. Adv Exp Med Biol 2007;594:14–26.
  27. Wyttenbach A, Sauvageot O, Carmichael J, Diaz-Latoud C, Arrigo AP, Rubinsztein DC: Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin. Hum Mol Genet 2002;11:1137–1151.
  28. Benndorf R, Welsh MJ: Shocking degeneration. Nat Genet 2004;36:547–548.
  29. Evgrafov OV, Mersiyanova I, Irobi J, Van Den Bosch L, Dierick I, Leung CL, Schagina O, Verpoorten N, Van Impe K, Fedotov V, Dadali E, Auer-Grumbach M, Windpassinger C, Wagner K, Mitrovic Z, Hilton-Jones D, Talbot K, Martin JJ, Vasserman N, Tverskaya S, Polyakov A, Liem RK, Gettemans J, Robberecht W, De Jonghe P, Timmerman V: Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet 2004;36:602–606.
  30. Wu C: Heat shock transcription factors: structure and regulation. Annu Rev Cell Dev Biol 1995;11:441–469.
  31. Kaarniranta K, Oksala N, Karjalainen HM, Suuronen T, Sistonen L, Helminen HJ, Salminen A, Lammi MJ: Neuronal cells show regulatory differences in the hsp70 gene response. Brain Res Mol Brain Res 2002;101:136–140.
  32. Batulan Z, Shinder GA, Minotti S, He BP, Doroudchi MM, Nalbantoglu J, Strong MJ, Durham HD: High threshold for induction of the stress response in motor neurons is associated with failure to activate HSF1. J Neurosci 2003;23:5789–5798.
  33. Khaleque MA, Bharti A, Sawyer D, Gong J, Benjamin IJ, Stevenson MA, Calderwood SK: Induction of heat shock proteins by heregulin β1 leads to protection from apoptosis and anchorage-independent growth. Oncogene 2005;24:6564–6573.
  34. Wang X, Grammatikakis N, Siganou A, Calderwood SK: Regulation of molecular chaperone gene transcription involves the serine phosphorylation, 14-3-3 epsilon binding, and cytoplasmic sequestration of heat shock factor 1. Mol Cell Biol 2003;23:6013–6026.
  35. Shamovsky I, Ivannikov M, Kandel ES, Gershon D, Nudler E: RNA-mediated response to heat shock in mammalian cells. Nature 2006;440:556–560.
  36. Chang R, Wang E: Mouse translation elongation factor eEF1A-2 interacts with Prdx-I to protect cells against apoptotic death induced by oxidative stress. J Cell Biochem 2007;100:267–278.
  37. Chu B, Soncin F, Price BD, Stevenson MA, Calderwood SK: Sequential phosphorylation by mitogen-activated protein kinase and glycogen synthase kinase 3 represses transcriptional activation by heat shock factor-1. J Biol Chem 1996;271:30847–30857.
  38. Bhat RV, Budd Haeberlein SL, Avila J: Glycogen synthase kinase 3: a drug target for CNS therapies. J Neurochem 2004;89:1313–1317.
  39. Takahashi R, Imai Y: Pael receptor, endoplasmic reticulum stress, and Parkinson’s disease. J Neurol 2003;250(suppl 3):III25–III29.
  40. Jana NR, Dikshit P, Goswami A, Kotliarova S, Murata S, Tanaka K, Nukina N: Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes. J Biol Chem 2005;280:11635–11640.