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The role of Hsp70 in oxi-inflamm-aging and its use as a potential biomarker of lifespan

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Abstract

The heat-shock protein 70 (HSPA1A or Hsp70) acts as a cellular defense mechanism its expression being induced under stressful conditions. Aging has been related to an impairment in this induction. However, an extended longevity has been associated with its increased expression. According to the oxidation-inflammation theory of aging, chronic oxidative stress and inflammatory stress situations (with higher levels of oxidant and inflammatory compounds and lower antioxidant and anti-inflammatory defenses) are the basis of the age-related alterations of body cells. Since oxidation and inflammation are interlinked processes, and Hsp70 has been shown to confer protection against the harmful effects of oxidative stress as well as modulating the inflammatory status, it could play a role as a regulator of the rate of aging. This role may be different in mitotic and post-mitotic tissues due to the differences in their age-related mechanisms of response, such as apoptosis. Mechanisms affected by Hsp70 that can interfere with the deleterious effects of excessive oxidative stress and chronic low-grade inflammation and that are closely related to the aging process have been detailed. In addition, the potential use of the basal levels (with their differences in post-mitotic and mitotic tissues), the inducible levels, as well as the extracellular levels of Hsp70 as possible biomarkers of the rate of aging and lifespan, have also been discussed.

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References

  • 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 39:1475–1484

    Article  CAS  PubMed  Google Scholar 

  • Arranz L, Caamaño JH, Lord JM, De La Fuente M (2010) Preserved immune functions and controlled leukocyte oxidative stress in naturally long-lived mice: possible role of nuclear factor kappa B. J Gerontol A 65A:941–950

    Article  CAS  Google Scholar 

  • Asea A et al (2002) Novel signal transduction pathway utilized by extracellular HSP70. Role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277:15028–15034

    Article  CAS  PubMed  Google Scholar 

  • Barja G (2004) Free radicals and aging. Trends Neurosci 27:595–600

    Article  CAS  PubMed  Google Scholar 

  • Bausero MA, Gastpar R, Multhoff G, Asea A (2005) Alternative mechanism by which IFN-γ enhances tumor recognition: active release of heat shock protein 72. J Immunol 175:2900–2912

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Beere HM et al (2000) Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2:469–475

    Article  CAS  PubMed  Google Scholar 

  • Broome CS, Kayani AC, Palomero J, Dillmann WH, Mestril R, Jackson MJ, McArdle A (2006) Effect of lifelong overexpression of HSP70 in skeletal muscle on age-related oxidative stress and adaptation after nondamaging contractile activity. FaseB J 20:1549–1551

    Article  CAS  PubMed  Google Scholar 

  • Broquet AH, Thomas G, Masliah J, Trugnan G, Bachelet M (2003) Expression of the molecular chaperone Hsp70 in detergent-resistant microdomains correlates with its membrane delivery and release. J Biol Chem 278:21601–21606

    Article  CAS  PubMed  Google Scholar 

  • Buzzard KA, Giaccia AJ, Killender M, Anderson RL (1998) Heat shock protein 72 modulates pathways of stress-induced apoptosis. J Biol Chem 273:17147–17153

    Article  CAS  PubMed  Google Scholar 

  • Calderwood SK, Mambula SS, Gray PJ Jr, Theriault JR (2007) Extracellular heat shock proteins in cell signaling. FEBS Lett 581:3689–3694

    Article  CAS  PubMed  Google Scholar 

  • Clayton A, Turkes A, Navabi H, Mason MD, Tabi Z (2005) Induction of heat shock proteins in B-cell exosomes. J Cell Sci 118:3631–3638

    Article  CAS  PubMed  Google Scholar 

  • Colotti C et al (2005) Effects of aging and anti-aging caloric restrictions on carbonyl and heat shock protein levels and expression. Biogerontology 6:397–406

    Article  CAS  PubMed  Google Scholar 

  • De La Fuente M (2014) Editorial crosstalk between the nervous and the immune systems in health and sickness. Curr Pharm Des 20:4605–4607

    Article  PubMed  Google Scholar 

  • De La Fuente M, Miquel J (2009) An update of the oxidation-inflammation theory of aging: the involvement of the immune system in Oxi-Inflamm-Aging. Curr Pharm Des 15:3003–3026

    Article  PubMed  Google Scholar 

  • Deguchi Y, Negoro S, Kishimoto S (1988) Age-related changes of heat shock protein gene transcription in human peripheral blood mononuclear cells. Biochem Biophys Res Commun 157:580–584

    Article  CAS  PubMed  Google Scholar 

  • Demirovic D, Rattan SIS (2013) Establishing cellular stress response profiles as biomarkers of homeodynamics, health and hormesis. Exp Gerontol 48:94–98

    Article  CAS  PubMed  Google Scholar 

  • Demirovic D, MartínezdeToda I, Rattan SIS (2013) Molecular stress response pathways as the basis of hormesis. In: Hormesis in human health and disease. CRC Press, Boca Raton, pp 227–241

  • Ding XZ, Fernandez-Prada CM, Bhattacharjee AK, Hoover DL (2001) Over-expression of HSP-70 inhibits bacterial lipopolysaccharide-induced production of cytokines in human monocyte-derived macrophages. Cytokine 16:210–219

    Article  CAS  PubMed  Google Scholar 

  • 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. P Natl Acad Sci USA 87:846–850

    Article  CAS  Google Scholar 

  • Fonager J, Beedholm R, Clark BFC, Rattan SIS (2002) Mild stress-induced stimulation of heat-shock protein synthesis and improved functional ability of human fibroblasts undergoing aging in vitro. Exp Gerontol 37:1223–1228

    Article  CAS  PubMed  Google Scholar 

  • Franceschi C, BonafÈ M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging: an evolutionary perspective on immunosenescence. Ann NY Acad Sci 908:244–254

    Article  CAS  PubMed  Google Scholar 

  • Gabai VL, Mabuchi K, Mosser DD, Sherman MY (2002) Hsp72 and stress kinase c-jun N-terminal kinase regulate the Bid-dependent pathway in tumor necrosis factor-induced apoptosis. Mol Cell Biol 22:3415–3424

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ganter MT et al (2006) Extracellular heat shock protein 72 is a marker of the stress protein response in acute lung injury. Am J Physiol 291:L354–L361

    CAS  Google Scholar 

  • Gao T, Newton AC (2002) The turn motif is a phosphorylation switch that regulates the binding of Hsp70 to protein kinase C. J Biol Chem 277:31585–31592

    Article  CAS  PubMed  Google Scholar 

  • Gastpar R, Gehrmann M, Bausero MA, Asea A, Gross C, Schroeder JA, Multhoff G (2005) Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res 65:5238–5247

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gilmore TD (2006) Introduction to NF-κB: players, pathways, perspectives. Oncogene 25:6680–6684

    Article  CAS  PubMed  Google Scholar 

  • Giraldo E, Hinchado MD, Ortega E (2013) Combined activity of post-exercise concentrations of NA and eHsp72 on human neutrophil function: role of cAMP. J Cell Physiol 228:1902–1906

    Article  CAS  PubMed  Google Scholar 

  • Gleixner AM, Pulugulla SH, Pant DB, Posimo JM, Crum TS, Leak RK (2014) Impact of aging on heat shock protein expression in the substantia nigra and striatum of the female rat. Cell Tissue Res 357:43–54

    Article  CAS  PubMed  Google Scholar 

  • Gross C, Schmidt-Wolf IGH, Nagaraj S, Gastpar R, Ellwart J, Kunz-Schughart LA, Multhoff G (2003) Heat shock protein 70-reactivity is associated with increased cell surface density of CD94/CD56 on primary natural killer cells. Cell Stress Chaperon 8:348–360

    Article  CAS  Google Scholar 

  • Guo F et al (2005) Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells. Blood 105:1246–1255

    Article  CAS  PubMed  Google Scholar 

  • Guzhova IV, Darieva ZA, Melo AR, Margulis BA (1997) Major stress protein Hsp70 interacts with NF-kB regulatory complex in human T-lymphoma cells. Cell Stress Chaperon 2:132–139

    Article  CAS  Google Scholar 

  • Guzhova I, Kislyakova K, Moskaliova O, Fridlanskaya I, Tytell M, Cheetham M, Margulis B (2001) In vitro studies show that Hsp70 can be released by glia and that exogenous Hsp70 can enhance neuronal stress tolerance. Brain Res 914:66–73

    Article  CAS  PubMed  Google Scholar 

  • Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300

    Article  CAS  PubMed  Google Scholar 

  • Heydari AR, Takahashi R, Gutsmann A, You S, Richardson A (1994) Hsp70 and aging. Experientia 50:1092–1098

    Article  CAS  PubMed  Google Scholar 

  • Hightower LE, Guidon PT Jr (1989) Selective release from cultured mammalian cells of heat-shock (stress) proteins that resemble glia-axon transfer proteins. J Cell Physiol 138:257–266

    Article  CAS  PubMed  Google Scholar 

  • Hinchado MD, Giraldo E, Ortega E (2012) Adrenoreceptors are involved in the stimulation of neutrophils by exercise-induced circulating concentrations of Hsp72: cAMP as a potential “intracellular danger signal”. J Cell Physiol 227:604–608

    Article  CAS  PubMed  Google Scholar 

  • Hunter-Lavin C, Davies EL, Bacelar MMFVG, Marshall MJ, Andrew SM, Williams JHH (2004) Hsp70 release from peripheral blood mononuclear cells. Biochem Biophys Res Commun 324:511–517

    Article  CAS  PubMed  Google Scholar 

  • Kampinga HH et al (2009) Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperon 14:105–111

    Article  CAS  Google Scholar 

  • Kovalchin JT, Wang R, Wagh MS, Azoulay J, Sanders M, Chandawarkar RY (2006) In vivo delivery of heat shock protein 70 accelerates wound healing by up-regulating macrophage-mediated phagocytosis. Wound Repair Regen 14:129–137

    Article  PubMed  Google Scholar 

  • Kregel KC, Moseley PL (1996) Differential effects of exercise and heat stress on liver HSP70 accumulation with aging. J Appl Physiol 80:547–551

    CAS  PubMed  Google Scholar 

  • Lancaster GI, Febbraio MA (2005) Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J Biol Chem 280:23349–23355

    Article  CAS  PubMed  Google Scholar 

  • Lehner T, Wang Y, Whittall T, McGowan E, Kelly CG, Singh M (2004) Functional domains of HSP70 stimulate generation of cytokines and chemokines, maturation of dendritic and adjuvanticity. Biochem Soc Trans 32:629–632

    Article  CAS  PubMed  Google Scholar 

  • Liberek K, Lewandowska A, Ziȩtkiewicz S (2008) Chaperones in control of protein disaggregation. EMBO J 27:328–335

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Liu AY, Lee YK, Manalo D, Huang LE (1996) Attenuated heat shock transcriptional response in aging: molecular mechanism and implication in the biology of aging. EXS 77:393–408

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Mambula SS, Stevenson MA, Ogawa K, Calderwood SK (2007) Mechanisms for Hsp70 secretion: crossing membranes without a leader. Methods 43:168–175

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mathew A, Bell A, Johnstone RM (1995) Hsp-70 is closely associated with the transferrin receptor in exosomes from maturing reticulocytes. Biochem J 308:823–830

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Matthews JR, Hay RT (1995) Regulation of the DNA binding activity of NF-κB. Int J Biochem Cell B 27:865–879

    Article  CAS  Google Scholar 

  • Multhoff G, Pfister K, Gehrmann M, Hantschel M, Gross C, Hafner M, Hiddemann W (2001) A 14-mer Hsp70 peptide stimulates natural killer (NK) cell activity. Cell Stress Chaperon 6:337–344

    Article  CAS  Google Scholar 

  • Nakanishi Y, Yasumoto K (1997) Induction after administering paraquat of heme oxygenase-1 and heat shock protein 70 in the liver of senescence-accelerated mice. Biosci Biotech Biochem 61:1302–1306

    Article  CAS  Google Scholar 

  • 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 

  • Njemini R, Demanet C, Mets T (2004) Inflammatory status as an important determinant of heat shock protein 70 serum concentrations during aging. Biogerontology 5:31–38

    Article  CAS  PubMed  Google Scholar 

  • Ortega E, Bote ME, Besedovsky HO, Rey AD (2012) Hsp72, inflammation, and aging: causes, consequences, and perspectives. Ann NY Acad Sci 1261:64–71

    Article  CAS  PubMed  Google Scholar 

  • Pahlavani MA, Harris MD, Moore SA, Weindruch R, Richardson A (1995) The expression of heat shock protein 70 decreases with age in lymphocytes from rats and rhesus monkeys. Exp Cell Res 218:310–318

    Article  CAS  PubMed  Google Scholar 

  • Pockley AG, Shepherd J, Corton JM (1998) Detection of heat shock protein 70 (Hsp70) and anti-Hsp70 antibodies in the serum of normal individuals. Immunol Invest 27:367–377

    Article  CAS  PubMed  Google Scholar 

  • Polla BS, Stubbe H, Kantengwa S, Maridonneau-Parini I, Jacquier-Sarlin MR (1995) Differential induction of stress proteins and functional effects of heat shock in human phagocytes. Inflammation 19:363–378

    Article  CAS  PubMed  Google Scholar 

  • Polla BS, Kantengwa S, François D, Salvioli S, Franceschi C, Marsac C, Cossarizza A (1996) Mitochondria are selective targets for the protective effects of heat shock against oxidative injury. P Natl Acad Sci USA 93:6458–6463

    Article  CAS  Google Scholar 

  • Rea IM, McNerlan S, Pockley AG (2001) Serum heat shock protein and anti-heat shock protein antibody levels in aging. Exp Gerontol 36:341–352

    Article  CAS  PubMed  Google Scholar 

  • Rea SL, Wu D, Cypser JR, Vaupel JW, Johnson TE (2005) A stress-sensitive reporter predicts longevity in isogenic populations of Caenorhabditis elegans. Nat Genet 37:894–898

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Richter K, Haslbeck M, Buchner J (2010) The heat shock response: life on the verge of death. Mol Cell 40:253–266

    Article  CAS  PubMed  Google Scholar 

  • Salway KD, Gallagher EJ, Page MM, Stuart JA (2011) Higher levels of heat shock proteins in longer-lived mammals and birds. Mech Ageing Dev 132:287–297

    Article  CAS  PubMed  Google Scholar 

  • Schmitt E, Gehrmann M, Brunet M, Multhoff G, Garrido C (2007) Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy. J Leukocyte Biol 81:15–27

    Article  CAS  PubMed  Google Scholar 

  • Senf SM (2013) Skeletal muscle heat shock protein 70: diverse functions and therapeutic potential for wasting disorders. Front Physiol 11(4):330

    Google Scholar 

  • Shamovsky I, Gershon D (2004) Novel regulatory factors of HSF-1 activation: facts and perspectives regarding their involvement in the age-associated attenuation of the heat shock response. Mech Ageing Dev 125:767–775

    Article  CAS  PubMed  Google Scholar 

  • Singh R et al (2006) Reduced heat shock response in human mononuclear cells during aging and its association with polymorphisms in HSP70 genes. Cell Stress Chaperon 11:208–215

    Article  CAS  Google Scholar 

  • Singh R, Kolvraa S, Rattan SIS (2007) Genetics of human longevity with emphasis on the relevance of HSP70 as candidate genes. Front Biosci 12:4504–4513

    Article  CAS  PubMed  Google Scholar 

  • Söti C, Csermely P (2000) Molecular chaperones and the aging process. Biogerontology 1:225–233

    Article  PubMed  Google Scholar 

  • Svensson PA et al (2006) Major role of HSP70 as a paracrine inducer of cytokine production in human oxidized LDL treated macrophages. Atherosclerosis 185:32–38

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tavaria M, Gabriele T, Kola I, Anderson RL (1996) A hitchhiker’s guide to the human Hsp70 family. Cell Stress Chaperon 1:23–28

    Article  CAS  Google Scholar 

  • Taylor AR, Robinson MB, Gifondorwa DJ, Tytell M, Milligan CE (2007) Regulation of heat shock protein 70 release in astrocytes: role of signaling kinases. Dev Neurobiol 67:1815–1829

    Article  CAS  PubMed  Google Scholar 

  • Terry DF et al (2004) Cardiovascular disease delay in centenarian offspring: role of heat shock proteins. Ann NY Acad Sci 1019:502–505

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Théry C et al (1999) Molecular characterization of dendritic cell-derived exosomes: selective accumulation of the heat shock protein hsc73. J Cell Biol 147:599–610

    Article  PubMed Central  PubMed  Google Scholar 

  • Vabulas RM, Ahmad-Nejad P, Ghose S, Kirschning CJ, Issels RD, Wagner H (2002) HSP70 as endogenous stimulus of the toll/interleukin-1 receptor signal pathway. J Biol Chem 277:15107–15112

    Article  CAS  PubMed  Google Scholar 

  • Van Molle W, Wielockx B, Mahieu T, Takada M, Taniguchi T, Sekikawa K, Libert C (2002) HSP70 protects against TNF-induced lethal inflammatory shock. Immunity 16:685–695

    Article  PubMed  Google Scholar 

  • Van Eden W, Van Der Zee R, Prakken B (2005) Heat-shock proteins induce T-cell regulation of chronic inflammation. Nat Rev Immunol 5:318–330

    Article  PubMed  Google Scholar 

  • Vasto S et al (2007) Inflammatory networks in ageing, age-related diseases and longevity. Mech Ageing Dev 128:83–91

    Article  CAS  PubMed  Google Scholar 

  • Vega VL et al (2008) Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J Immunol 180:4299–4307

    Article  CAS  PubMed  Google Scholar 

  • Verbeke P, Fonager J, Clark BFC, Rattan SIS (2001) Heat shock response and ageing: mechanisms and applications. Cell Biol Int 25:845–857

    Article  CAS  PubMed  Google Scholar 

  • Vida C, González EM, De la Fuente M (2014) Increase of oxidation and inflammation in nervous and immune systems with aging and anxiety. Curr Pharm Design 20:4656–4678

    Article  CAS  Google Scholar 

  • Wheeler JC, Bieschke ET, Tower J (1995) Muscle-specific expression of Drosophila hsp70 in response to aging and oxidative stress. Proc Natl Acad Sci USA 92:10408–10412

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wong HR, Ryan M, Wispé JR (1997) The heat shock response inhibits inducible nitric oxide synthase gene expression by blocking Iκ-B degradation and NF-κB nuclear translocation. Biochem Biophys Res Commun 231:257–263

    Article  CAS  PubMed  Google Scholar 

  • Zheng Z, Kim JY, Ma H, Lee JE, Yenari MA (2008) Anti-inflammatory effects of the 70 kDa heat shock protein in experimental stroke. J Cerebr Blood Flow Metab 28:53–63

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by g rants of the MINECO (BFU2011-30336), FIS (PI15/01787), Research group of UCM (910379) and RETICEF (RD12/0043/0018) from the ISCIII-FEDER of the European Union.

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de Toda, I.M., De la Fuente, M. The role of Hsp70 in oxi-inflamm-aging and its use as a potential biomarker of lifespan. Biogerontology 16, 709–721 (2015). https://doi.org/10.1007/s10522-015-9607-7

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