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Glycerol stimulates innate chaperoning, proteasomal and stress-resistance functions: implications for geronto-manipulation

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Abstract

Aging is associated with accumulation of toxic intracellular and extracellular protein aggregates. Cells manage “aged” proteins by mobilizing their molecular chaperones or heat shock proteins that are also considered as determinants of lifespan in diverse species. In this study, we tested whether an exogenous addition of the non-toxic chemical chaperone ‘glycerol’ could elicit stress and geronto-protective activities. We found that glycerol enhanced chaperoning of heat-denatured proteins. In addition to stimulating proteasome activity, glycerol led to an increased expression of the stress chaperone ‘mortalin’ and decreased p53 function in human cells. Glycerol-fed worms exhibited thermo-tolerance and lower level of age-associated auto-fluorescence. Through the combined stimulation of the proteasome and chaperoning activities of mortalin, in particular, glycerol treatment resulted in increased survival and fitness against oxidative- and heat-stress. These results may have significant implications in the use of glycerol as a candidate geronto-modulator in development of practical interventions for “healthy aging”.

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References

  • Bai C, Biwersi J, Verkman AS, Matthay MA (1998) A mouse model to test the in vivo efficacy of chemical chaperones. J Pharmacol Toxicol Methods 40:39–45

    Article  PubMed  CAS  Google Scholar 

  • Ballinger CA, Connell P, Wu Y, Hu Z, Thompson LJ, Yin LY, Patterson C (1999) Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol 19:4535–4545

    PubMed  CAS  Google Scholar 

  • Bayer AJ, Pathy MS, Newcombe R (1987) Double-blind randomised trial of intravenous glycerol in acute stroke. Lancet 1:405–408

    Article  PubMed  CAS  Google Scholar 

  • Benaroudj N, Lee DH, Goldberg AL (2001) Trehalose accumulation during cellular stress protects cells and cellular proteins from damage by oxygen radicals. J Biol Chem 276:24261–24267

    Article  PubMed  CAS  Google Scholar 

  • Berger C, Sakowitz OW, Kiening KL, Schwab S (2005) Neurochemical monitoring of glycerol therapy in patients with ischemic brain edema. Stroke 36:e4–e6

    Article  PubMed  CAS  Google Scholar 

  • Brown CR, Hong-Brown LQ, Biwersi J, Verkman AS, Welch WJ (1996) Chemical chaperones correct the mutant phenotype of the delta F508 cystic fibrosis transmembrane conductance regulator protein. Cell Stress Chaperones 1:117–125

    Article  PubMed  CAS  Google Scholar 

  • Campisi J (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120:513–522

    Article  PubMed  CAS  Google Scholar 

  • Chavez Zobel AT, Loranger A, Marceau N, Theriault JR, Lambert H, Landry J (2003) Distinct chaperone mechanisms can delay the formation of aggresomes by the myopathy-causing R120G alphaB-crystallin mutant. Hum Mol Genet 12:1609–1620

    Article  PubMed  CAS  Google Scholar 

  • Chondrogianni N, Gonos ES (2005) Proteasome dysfunction in mammalian aging: steps and factors involved. Exp Gerontol 40:931–938

    Article  PubMed  CAS  Google Scholar 

  • Chou TC, Motzer RJ, Tong Y, Bosl GJ (1994) Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design. J Natl Cancer Inst 86:1517–1524

    Article  PubMed  CAS  Google Scholar 

  • Conconi M, Friguet B (1997) Proteasome inactivation upon aging and on oxidation-effect of HSP 90. Mol Biol Rep 24:45–50

    Article  PubMed  CAS  Google Scholar 

  • Dahlmann B, Becher B, Sobek A, Ehlers C, Kopp F, Kuehn L (1993) In vitro activation of the 20S proteasome. Enzyme Protein 47:274–284

    PubMed  CAS  Google Scholar 

  • de Jong JC, Willems PH, Goossens M, Vandewalle A, van den Heuvel LP, Knoers N. V, Bindels RJ (2004) Effects of chemical chaperones on partially retarded NaCl cotransporter mutants associated with Gitelman’s syndrome in a mouse cortical collecting duct cell line. Nephol Dial Transplant 19:1069–1076

    Article  CAS  Google Scholar 

  • Deocaris CC, Shrestha BG, Kraft DC, Yamasaki K, Kaul SC, Rattan SI, Wadhwa R (2006) Geroprotection by glycerol: insights to its mechanisms and clinical potentials. Ann NY Acad Sci 1067:488–492

    Article  PubMed  CAS  Google Scholar 

  • Diamant S, Eliahu N, Rosenthal D, Goloubinoff P (2001) Chemical chaperones regulate molecular chaperones in vitro and in cells under combined salt and heat stresses. J Biol Chem 276:39586–39591

    Article  PubMed  CAS  Google Scholar 

  • Ehenfried JA, Evers BM, Chu KU, Townsend CM Jr, Thompson JC (1996) Caloric restriction increases the expression of heat shock protein in the gut. Ann Surg 223:592–597

    Article  Google Scholar 

  • Fisher AL, Lithgow GJ (2006) The nuclear hormone receptor DAF-12 has opposing effects on Caenorhabditis elegans lifespan and regulates genes repressed in multiple long-lived worms. Aging Cell 5:127–138

    Article  PubMed  CAS  Google Scholar 

  • Frigeri A, Gropper MA, Umenishi F, Kawashima M, Brown D, Verkman AS (1995) Localization of MIWC and GLIP water channel homologs in neuromuscular, epithelial and glandular tissues. J Cell Sci 108:2993–3002

    PubMed  CAS  Google Scholar 

  • Gu Y, Singh N (2004) Doxycycline and protein folding agents rescue the abnormal phenotype of familial CJD H187R in a cell model. Brain Res Mol Brain Res 123:37–44

    Article  PubMed  CAS  Google Scholar 

  • Hansen MB, Nielsen SE, Berg K (1989) Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J Immunol Methods 119:203–210

    Article  PubMed  CAS  Google Scholar 

  • Hatayama T, Fujimoto S, Sakai K (1997) Effect of hyperosmotic NaCl and glycerol stress on stress response of human HeLa cells. Biol Pharm Bull 20:605–612

    PubMed  CAS  Google Scholar 

  • Ishikawa M, Sekizuka E, Sato S, Yamaguchi N, Inamasu J, Kawase T (1999) Glycerol attenuates the adherence of leukocytes in rat pial venules after transient middle cerebral artery occlusion. Neurol Res 21:785–790

    PubMed  CAS  Google Scholar 

  • Kaul SC, Reddel RR, Sugihara T, Mitsui Y, Wadhwa R (2000) Inactivation of p53 and life span extension of human diploid fibroblasts by mot-2. FEBS Lett 474:159–164

    Article  CAS  Google Scholar 

  • Kaul SC, Taira K, Pereira-Smith OM, Wadhwa R (2002) Mortalin: present and prospective. Exp Gerontol 37:1157–1164

    Article  PubMed  CAS  Google Scholar 

  • Kaul SC, Yaguchi T, Taira K, Reddel RR, Wadhwa R (2003) Overexpressed mortalin mot-2/mthsp70/GRP75 and hTERT cooperate to extend the in vitro lifespan of human fibroblasts. Exp Cell Res 286:96–101

    Article  PubMed  CAS  Google Scholar 

  • Kaul SC, Aida S, Yaguchi T, Kaur K, Wadhwa R (2005) Activation of wild type p53 function by its mortalin-binding, cytoplasmically localizing carboxyl terminus peptides. J Biol Chem 280:39373–39379

    Article  PubMed  CAS  Google Scholar 

  • Khodagholi F, Yazdanparast R (2005) Artificial chaperone-assisted refolding of GuHCl-denatured alpha-amylase at low temperature: refolding versus aggregation. Protein J 24:303–313

    Article  PubMed  CAS  Google Scholar 

  • Kim BE, Smith K, Meagher CK, Petris MJ (2002) A conditional mutation affecting localization of the Menkes disease copper ATPase. Suppression by copper supplementation. J Biol Chem 277:44079–44084

    Article  PubMed  CAS  Google Scholar 

  • Kirita T, Ohnishi K, Ohnishi T (2001) A new strategy for cancer therapy based on a predictive indicator. Hum Cell 14:1–6

    PubMed  CAS  Google Scholar 

  • Kuckelkorn U, Knuehl C, Boes-Fabian B, Drung I, Kloetzel PM (2000) The effect of heat shock on 20S/26S proteasomes. Biol Chem 381:1017–1023

    Article  PubMed  CAS  Google Scholar 

  • Lahiri DK, Chen DM, Lahiri P, Bondy S, Greig NH (2005) Amyloid, cholinesterase, melatonin, and metals and their roles in aging and neurodegenerative diseases. Ann NY Acad Sci 1056:430–449

    Article  PubMed  CAS  Google Scholar 

  • Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–331

    Article  PubMed  CAS  Google Scholar 

  • Li D, Sun F, Wang K (2004) Protein profile of aging and its retardation by caloric restriction in neural retina. Biochem Biophys Res Commun 318:253–258

    Article  PubMed  CAS  Google Scholar 

  • Lissin NM (1995) In vitro dissociation of self-assembly of three chaperonin 60s: the role of ATP. FEBS Lett 361:55–60

    Article  PubMed  CAS  Google Scholar 

  • Liu M, Wang X, Yin C, Zhang Z, Lin Q, Zhen Y, Huang H (2006) One-step on-column purification and refolding of a single-chain variable fragment scFv antibody against tumour necrosis factor alpha. Biotechnol Appl Biochem 43:137–145

    Article  PubMed  CAS  Google Scholar 

  • Masoro EJ (2005) Overview of caloric restriction and ageing. Mech Ageing Dev 126:913–922

    Article  PubMed  CAS  Google Scholar 

  • Mendrysa SM, Perry ME (2006) Tumor suppression by p53 without accelerated aging: just enough of a good thing? Cell Cycle 5:714–717

    PubMed  CAS  Google Scholar 

  • Meng F, Park Y, Zhou H (2001) Role of proline, glycerol, and heparin as protein folding aids during refolding of rabbit muscle creatine kinase. Int J Biochem Cell Biol 33:701–709

    Article  PubMed  CAS  Google Scholar 

  • Meriin AB, Sherman MY (2005) Role of molecular chaperones in neurodegenerative disorders. Int J Hyperthermia 21:403–419

    Article  PubMed  CAS  Google Scholar 

  • Morello JP, Petaja-Repo UE, Bichet DG, Bouvier M (2000) Pharmacological chaperones: a new twist on receptor folding. Trends Pharmacol Sci 21:466–469

    Article  PubMed  CAS  Google Scholar 

  • Nagao Y, Ishiguro H, Nukina N (2000) DMSO and glycerol reduce bacterial death induced by expression of truncated N-terminal huntingtin with expanded polyglutamine tracts. Biochim Biophys Acta 1502:247–256

    PubMed  CAS  Google Scholar 

  • Nath D, Rao M (2001) Artificial chaperone mediated refolding of xylanase from an alkalophilic thermophilic Bacillus sp. Implications for in vitro protein renaturation via a folding intermediate. Eur J Biochem 268:5471–5478

    Article  PubMed  CAS  Google Scholar 

  • Nollen EA, Salomons FA, Brunsting JF, Want JJ, Sibon OC, Kampinga HH (2001) Dynamic changes in the localization of thermally unfolded nuclear proteins associated with chaperone-dependent protection. Proc Natl Acad Sci USA 98:12038–12043

    Article  PubMed  CAS  Google Scholar 

  • Ohnishi K, Ohnishi T (2001) Heat-induced p53-dependent signal transduction and its role in hyperthermic cancer therapy. Int J Hyperthermia 17:415–427

    Article  PubMed  CAS  Google Scholar 

  • Ohnishi T, Matsumoto H, Wang X, Takahashi A, Tamamoto T, Ohnishi K (1999) Restoration by glycerol of p53-dependent apoptosis in cells bearing the mutant p53 gene. Int J Radiat Biol 75:1095–1098

    Article  PubMed  CAS  Google Scholar 

  • Ohnishi K, Ota I, Takahashi A, Ohnishi T (2000) Glycerol restores p53-dependent radiosensitivity of human head and neck cancer cells bearing mutant p53. Br J Cancer 83:1735–1739

    Article  PubMed  CAS  Google Scholar 

  • Ohnishi K, Ota I, Yane K, Takahashi A, Yuki K, Emoto M, Hosoi H, Ohnishi T (2002a) Glycerol as a chemical chaperone enhances radiation-induced apoptosis in anaplastic thyroid carcinoma cells. Mol Cancer 1:4

    Article  PubMed  Google Scholar 

  • Ohnishi T, Ohnishi K, Takahashi A (2002b) Glycerol restores heat-induced p53-dependent apoptosis of human glioblastoma cells bearing mutant p53. BMC Biotechnol 2:6

    Article  PubMed  Google Scholar 

  • Olson RD, Mushlin PS (1990) Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. FASEB J 4:3076–3086

    PubMed  CAS  Google Scholar 

  • Park YD, Wu BN, Tian WX, Zhou HM (2002) Effects of osmolytes on unfolding of chicken liver fatty acid synthase. Biochem Mosc 67:914–917

    Article  CAS  Google Scholar 

  • Rattan SI, Clark BF (2005) Understanding and modulating ageing. IUBMB Life 57:297–304

    Article  PubMed  CAS  Google Scholar 

  • Russell RJ, Ferguson JM, Hough DW, Danson MJ, Taylor GL (1997) The crystal structure of citrate synthase from the hyperthermophilic archaeon Pyrococcus furiosus at 1.9 A resolution. Biochemistry 36:9983–9994

    Article  PubMed  CAS  Google Scholar 

  • Sakamaki M, Igarashi H, Nishiyama Y, Hagiwara H, Ando J, Chishiki T, Curran BC, Katayama Y (2003) Effect of glycerol on ischemic cerebral edema assessed by magnetic resonance imaging. J Neurol Sci 209:69–74

    Article  PubMed  CAS  Google Scholar 

  • Scheper W, Hol EM (2005) Protein quality control in Alzheimer’s disease: a fatal saviour. Curr Drug Targets CNS Neurol Disord 4:283–292

    Article  PubMed  CAS  Google Scholar 

  • Shingarpure R, Davies KJ (2002) Protein turnover by the proteasome in aging and disease. Free Radic Biol Med 32:1084–1089

    Article  Google Scholar 

  • Sivakama Sundari C, Raman B, Balasubramanian D (1999) Artificial chaperoning of insulin, human carbonic anhydrase and hen egg lysozyme using linear dextrin chains–a sweet route to the native state of globular proteins. FEBS Lett 443:215–219

    Article  PubMed  CAS  Google Scholar 

  • Soti C, Csermely P (2002) Chaperones come of age. Cell Stress Chaperones 7:186–190

    Article  PubMed  CAS  Google Scholar 

  • Soti C, Csermely P (2003) Aging and molecular chaperones. Exp Gerontol 38:1037–1040

    Article  PubMed  CAS  Google Scholar 

  • Tamarappoo BK, Yang B, Verkman AS (1999) Misfolding of mutant aquaporin-2 water channels in nephrogenic diabetes insipidus. J Biol Chem 274:34825–34831

    Article  PubMed  CAS  Google Scholar 

  • Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, Kurosawa M, Nekooki M, Nukina N (2004) Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 10:148–154

    Article  PubMed  CAS  Google Scholar 

  • Thomas AR, Oosthuizen V, Naude RJ (2005) Differential effects of detergents, fatty acids, cations and heating on ostrich skeletal muscle 20S proteasome. Comp Biochem Physiol B Biochem Mol Biol 140:343–348

    Article  PubMed  CAS  Google Scholar 

  • Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C et al (2002) p53 mutant mice that display early ageing-associated phenotypes. Nature 415:45–53

    Article  PubMed  CAS  Google Scholar 

  • Voziyan PA, Jadhav L, Fisher MT (2000) Refolding a glutamine synthetase truncation mutant in vitro: identifying superior conditions using a combination of chaperonins and osmolytes. J Pharm Sci 89:1036–1045

    Article  PubMed  CAS  Google Scholar 

  • Wadhwa R, Takano S, Robert M, Yoshida A, Nomura H, Reddel RR, Mitsui Y, Kaul SC (1998) Inactivation of tumor suppressor p53 by mot-2, a hsp70 family member. J Biol Chem 273:29586–29591

    Article  PubMed  CAS  Google Scholar 

  • Wagner BJ, Margolis JW (1993) Thermal stability and activation of bovine lens multicatalytic proteinase complex proteasome. Arch Biochem Biophys 307:146–152

    Article  PubMed  CAS  Google Scholar 

  • Wang K, Spector A (2000) Alpha-crystallin prevents irreversible protein denaturation and acts cooperatively with other heat-shock proteins to renature the stabilized partially denatured protein in an ATP-dependent manner. Eur J Biochem 267:4705–4712

    Article  PubMed  CAS  Google Scholar 

  • Xie Q, Matsunaga S, Shi X, Ogawa S, Niimi S, Wen Z, Tokuyasu K, Machida S (2003) Refolding and characterization of the functional ligand-binding domain of human lectin-like oxidized LDL receptor. Protein Expr Purif 32:68–74

    Article  PubMed  CAS  Google Scholar 

  • Yazdanparast R, Khodagholi F, Khodagholi R (2005) Artificial chaperone-assisted refolding of chemically denatured alpha-amylase. Int J Biol Macromol 35:257–263

    Article  PubMed  CAS  Google Scholar 

  • Yoshimoto N, Hashimoto T, Felix MM, Umakoshi H, Kuboi R (2003) Artificial chaperone-assisted refolding of bovine carbonic anhydrase using molecular assemblies of stimuli-responsive polymers. Biomacromol 4:1530–1538

    Article  CAS  Google Scholar 

  • Yu YL, Kumana CR, Lauder IJ, Cheung YK, Chan FL, Kou M, Fong KY, Cheung RT, Chang CM (1993) Treatment of acute cortical infarct with intravenous glycerol. A double-blind, placebo-controlled randomized trial. Stroke 24:1119–1124

    PubMed  CAS  Google Scholar 

  • Zhao Q, Wang J, Levichkin IV, Stasinopoulos S, Ryan MT, Hoogenraad NJ (2002) A mitochondrial specific stress response in mammalian cells. EMBO J 21:4411–4419

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. National Institute of Advanced Industrial Science & Technology (AIST), Central 4, 1-1-1 Higashi, Tsukuba, 305 8562, Japan

    Custer C. Deocaris, Didik Priyandoko, Zeenia Kaul, Tomoko Yaguchi, Kazuhiko Yamasaki, Sunil C. Kaul & Renu Wadhwa

  2. Institute of Health and Sports Sciences, Tsukuba University, 1-1-1 Tennoudai, Tsukuba, Japan

    Custer C. Deocaris

  3. Department of Cellular & Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, USA

    Syuichi Takano

  4. Laboratory of Cellular Aging, Department of Molecular Biology, University of Aarhus, Aarhus, Denmark

    David C. Kraft

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  1. Custer C. Deocaris
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  2. Syuichi Takano
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  3. Didik Priyandoko
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  4. Zeenia Kaul
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Correspondence to Renu Wadhwa.

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Custer C. Deocaris and Syuichi Takano contributed equally to this work.

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Deocaris, C.C., Takano, S., Priyandoko, D. et al. Glycerol stimulates innate chaperoning, proteasomal and stress-resistance functions: implications for geronto-manipulation. Biogerontology 9, 269–282 (2008). https://doi.org/10.1007/s10522-008-9136-8

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