, Volume 7, Issue 5–6, pp 383–389 | Cite as

Protein homeostasis and molecular chaperones in aging

  • Mehmet Alper Arslan
  • Péter Csermely
  • Csaba Sőti
Review Article


Molecular chaperones are ubiquitous, highly conserved proteins responsible for the maintenance of protein folding homeostasis in cells. Environmental stress causes proteotoxic damage, which triggers chaperone induction and the subsequent reparation of cellular damage by chaperones, including disposing irreparable protein ensembles. We summarize the current view of protein damage, turnover, the stress response and chaperone function in aging, and review novel data showing that accumulation of misfolded proteins outcompete and overload the limited resources of the protein folding, maintenance and turnover system, compromising general protein homeastasis and cellular function. Possible involvement of chaperones and proteolysis in immunosenescence is highlighted. Defects in zinc metabolism are also addressed in relation to aging and changes in chaperone levels.


Heat shock protein Stress protein Chaperones-chaperone overload Aging Neurodegenerative diseases Protein folding Protein damage Zinc Metallothionein Immune response 



94 kDa glucose regulated protein


Heat shock transcription factor


Heat shock protein, the number thereafter denotes molecular weight






Reactive oxygen species



Work in the authors’ laboratory was supported by research grants from the EU 6th Framework program (FP6506850, FP6518230), Hungarian Science Foundation (OTKA-F47281) and from the Hungarian National Research Initiative (1A/056/2004 and KKK-0015/3.0). C.S. is a Bolyai research Scholar of the Hungarian Academy of Sciences. The authors apologize for not citing a number of excellent publications due to space limitations.


  1. Ambra R, Mocchegiani E, Giacconi R, Canali R, Rinna A, Malavolta M, Virgili F (2004) Characterization of the hsp70 response in lymphoblasts from aged and centenarian subjects and differential effects of in vitro zinc supplementation. Exp Gerontol 39:1475–1484PubMedCrossRefGoogle Scholar
  2. Bauman JW, Liu J, Klaassen CD (1993) Production of metallothionein and heat-shock proteins in response to metals. Fundam Appl Toxicol 21:15–22PubMedCrossRefGoogle Scholar
  3. Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin–proteasome system by protein aggregation. Science 292:1552–1555PubMedCrossRefGoogle Scholar
  4. Bennett EJ, Bence NF, Jayakumar R, Kopito RR (2005) Global impairment of the ubiquitin–proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation. Mol Cell 17:351–365PubMedCrossRefGoogle Scholar
  5. Bulteau AL, Verbeke P, Petropoulos I, Chaffotte AF, Friguet B (2001) Proteasome inhibition in glyoxal-treated fibroblasts and resistance of glycated glucose-6-phosphate dehydrogenase to 20 S proteasome degradation in vitro. J Biol Chem 276:45662–45668PubMedCrossRefGoogle Scholar
  6. Capasso M, Jeng JM, Malavolta M, Mocchegiani E, Sensi SL (2005) Zinc dyshomeostasis: a key modulator of neuronal injury. J Alzheimers Dis 8:93–108PubMedGoogle Scholar
  7. Chondrogianni N, Gonos ES (2005) Proteasome dysfunction in mammalian aging: steps and factors involved. Exp Gerontol 40:931–938PubMedCrossRefGoogle Scholar
  8. Cloos PA, Christgau S (2004) Post-translational modifications of proteins: implications for aging, antigen recognition, and autoimmunity. Biogerontology 5:139–158PubMedCrossRefGoogle Scholar
  9. Conconi M, Szweda LI, Levine RL, Stadtman ER, Friguet B (1996) Age-related decline of rat liver multicatalytic proteinase activity and protection from oxidative inactivation by heat-shock protein 90. Arch Biochem Biophys 331:232–240PubMedCrossRefGoogle Scholar
  10. Csermely P (2001) Chaperone overload is a possible contributor to ‘civilization diseases’. Trends Genet 17:701–704PubMedCrossRefGoogle Scholar
  11. Csermely P (2006) Weak links: stabilizers of complex systems from proteins to social networks. Springer Verlag, HeidelbergGoogle Scholar
  12. Cuervo AM (2004) Autophagy: many paths to the same end. Mol Cell Biochem 263:55–72PubMedCrossRefGoogle Scholar
  13. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292–1295PubMedCrossRefGoogle Scholar
  14. Dantuma NP, Groothuis TA, Salomons FA, Neefjes J (2006) A dynamic ubiquitin equilibrium couples proteasomal activity to chromatin remodeling. J Cell Biol 173:19–26PubMedCrossRefGoogle Scholar
  15. Dobson CM (2003) Protein folding and misfolding. Nature 426:884–890PubMedCrossRefGoogle Scholar
  16. Friguet B (2006) Oxidized protein degradation and repair in ageing and oxidative stress. FEBS Lett Epub ahead of print, doi:10.1016/j.febslet.2006.03.028Google Scholar
  17. Garigan D, Hsu AL, Fraser AG, Kamath RS, Ahringer J, Kenyon C (2002) Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. Genetics 161:1101–1112PubMedGoogle Scholar
  18. Gidalevitz T, Ben-Zvi A, Ho KH, Brignull HR, Morimoto RI (2006) Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 311:1471–1474PubMedCrossRefGoogle Scholar
  19. Hatayama T, Asai Y, Wakatsuki T, Kitamura T, Imahara H (1993) Regulation of hsp70 synthesis induced by cupric sulfate and zinc sulfate in thermotolerant HeLa cells. J Biochem (Tokyo) 114:592–597Google Scholar
  20. Heydari AR, You S, Takahashi R, Gutsmann-Conrad A, Sarge KD, Richardson A (2000) Age-related alterations in the activation of heat shock transcription factor 1 in rat hepatocytes. Exp Cell Res 256:83–93PubMedCrossRefGoogle Scholar
  21. Hsu AL, Murphy CT, Kenyon C (2003) Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300:1142–1145PubMedCrossRefGoogle Scholar
  22. Kessler B, Hong X, Petrovic J, Borodovsky A, Dantuma NP, Bogyo M, Overkleeft HS, Ploegh H, Glas R (2003) Pathways accessory to proteasomal proteolysis are less efficient in major histocompatibility complex class I antigen production. J Biol Chem 278:10013–10021PubMedCrossRefGoogle Scholar
  23. Macario AJ, Conway de Macario E (2005) Sick chaperones, cellular stress, and disease. N Engl J Med 353:1489–1501PubMedCrossRefGoogle Scholar
  24. Massey AC, Kaushik S, Sovak G, Kiffin R, Cuervo AM (2006) Consequences of the selective blockage of chaperone-mediated autophagy. Proc Natl Acad Sci USA 103:5805–5810PubMedCrossRefGoogle Scholar
  25. Matsumoto G, Kim S, Morimoto RI (2006) Huntingtin and mutant SOD1 form aggregate structures with distinct molecular properties in human cells. J Biol Chem 281:4477–4485PubMedCrossRefGoogle Scholar
  26. Mocchegiani E, Giacconi R, Muti E, Rogo C, Bracci M, Muzzioli M, Cipriano C, Malavolta M (2004) Zinc, immune plasticity, aging, and successful aging: role of metallothionein. Ann N Y Acad Sci 1019:127–134PubMedCrossRefGoogle Scholar
  27. Morimoto RI (1998) Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev 12:3788–3796PubMedGoogle Scholar
  28. Morley JF, Morimoto RI (2004) Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol Biol Cell 15:657–664PubMedCrossRefGoogle Scholar
  29. Morley JF, Brignull HR, Weyers JJ, Morimoto RI (2002) The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc Natl Acad Sci USA 99:10417–10422PubMedCrossRefGoogle Scholar
  30. Mukai H, Isagawa T, Goyama E, Tanaka S, Bence NF, Tamura A, Ono Y, Kopito RR (2005) Formation of morphologically similar globular aggregates from diverse aggregation-prone proteins in mammalian cells. Proc Natl Acad Sci USA 102:10887–10892PubMedCrossRefGoogle Scholar
  31. Nardai G, Csermely P, Sőti C (2002) Chaperone function and chaperone overload in the aged. A preliminary analysis. Exp Gerontol 37:1257–1262PubMedCrossRefGoogle Scholar
  32. Nardai G, Vegh E, Prohaszka Z, Csermely P (2006) Chaperone-related immune dysfunctions: an emergent property of distorted chaperone-networks. Trends Immunol 27:74–79PubMedCrossRefGoogle Scholar
  33. Nollen EA, Garcia SM, van Haaften G, Kim S, Chavez A, Morimoto RI (2004) Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation. Proc Natl Acad Sci USA 101:6403–6408 PubMedCrossRefGoogle Scholar
  34. Parat MO, Richard MJ, Favier A, Beani JC (1998) Metal chelator N,N,N,N-tetrakis-(2-pyridymethyl)ethylene diamine inhibits the induction of heat shock protein 70 synthesis by heat in cultured keratinocytes. Biol Trace Elem Res 65:261–270PubMedGoogle Scholar
  35. Qing G, Duan X, Jiang Y (2004) Induction of heat shock protein 72 in RGCs of rat acute glaucoma model after heat stress or zinc administration. Yan Ke Xue Bao 20:30–33 (abstr)Google Scholar
  36. Rattan SI (2004) Aging intervention, prevention, and therapy through hormesis. J Gerontol A Biol Sci Med Sci 59:705–709PubMedGoogle Scholar
  37. Schaffar G, Breuer P, Boteva R, Behrends C, Tzvetkov N, Strippel N, Sakahira H, Siegers K, Hayer-Hartl M, Hartl FU (2004) Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol Cell 15:95–105PubMedCrossRefGoogle Scholar
  38. Sőti C, Csermely P (2000) Molecular chaperones and the aging process. Biogerontology 1:225–233PubMedCrossRefGoogle Scholar
  39. Sőti C, Csermely P (2003) Aging and molecular chaperones. Exp Gerontol 38:1037–1040PubMedCrossRefGoogle Scholar
  40. Sőti C, Pal C, Papp B, Csermely P (2005) Chaperones as regulatory elements of cellular networks. Curr Op Cell Biol 17:210–215PubMedCrossRefGoogle Scholar
  41. Stadtman ER (2004) Role of oxidant species in aging. Curr Med Chem 11:1105–1112PubMedGoogle Scholar
  42. Young JC, Agashe VR, Siegers K, Hartl FU (2004) Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol 5:781–791PubMedCrossRefGoogle Scholar
  43. Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, Naslund J, Mathews PM, Cataldo AM, Nixon RA (2005) Macroautophagy—a novel Beta-amyloid peptide-generating pathway activated in Alzheimer’s disease. J Cell Biol 171:87–98PubMedCrossRefGoogle Scholar
  44. Zhou H, Cao F, Wang Z, Yu ZX, Nguyen HP, Evans J, Li SH, Li XJ (2003) Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity. J Cell Biol 163:109–118PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, B.V. 2006

Authors and Affiliations

  • Mehmet Alper Arslan
    • 1
  • Péter Csermely
    • 1
  • Csaba Sőti
    • 1
  1. 1.Department of Medical ChemistrySemmelweis UniversityBudapest 8Hungary

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