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Chronic resveratrol intake reverses pro-inflammatory cytokine profile and oxidative DNA damage in ageing hybrid mice

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Abstract

Thymic involution and shrinkage of secondary lymphoid organs are leading causes of the deterioration of the T-cell compartment with age. Inflamm-aging, a sustained inflammatory status has been associated with chronic diseases and shortened longevity. This is the first study to investigate the effect of treating aging hybrid mice with long-term, low-dose resveratrol (RSV) in drinking water by assessing multiple immunological markers and profiles in the immune system. We found that hybrid mice exhibited marked age-related changes in the CD3+CD4+, C3+CD8+, CD4+CD25+, CD4M and CD8M surface markers. RSV reversed surface phenotypes of old mice to that of young mice by maintaining the CD4+ and CD8+ population in splenocytes as well as reducing CD8+CD44+ (CD8M) cells in the aged. RSV also enhanced the CD4+CD25+ population in old mice. Interestingly, pro-inflammatory status in young mice was transiently elevated by RSV but it consequently mitigated the age-dependent increased pro-inflammatory cytokine profile while preserving the anti-inflammatory cytokine condition in the old mice. Age-dependent increase in 8OHdG, an oxidative DNA damage marker was ameliorated by RSV. Immunological-focused microarray gene expression analysis showed that only the CD72 gene was significantly downregulated in the 12-month RSV-treated mice compared to age-matched controls. Our study indicates that RSV even at low physiological relevant levels is able to affect the immune system without causing marked gene expression changes.

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References

  • Adolfsson O, Huber BT, Meydani SN (2001) Vitamin E-enhanced IL-2 production in old mice: naive but not memory T cells show increased cell division cycling and IL-2-producing capacity. J Immunol 167(7):3809–3817

    PubMed  CAS  Google Scholar 

  • Alberti S, Cevenini E, Ostan R, Capri M, Salvioli S, Bucci L, Ginaldi L, De Martinis M, Franceschi C, Monti D (2006) Age-dependent modifications of type 1 and type 2 cytokines within virgin and memory CD4+ T cells in humans. Mech Ageing Dev 127(6):560–566

    Article  PubMed  CAS  Google Scholar 

  • Ansar Ahmed S, Dauphinee MJ, Montoya AI, Talal N (1989) Estrogen induces normal murine CD5+ B cells to produce autoantibodies. J Immunol 142(8):2647–2653

    PubMed  CAS  Google Scholar 

  • Aspinall R, Andrew D (2000) Thymic atrophy in the mouse is a soluble problem of the thymic environment. Vaccine 18(16):1629–1637

    Article  PubMed  CAS  Google Scholar 

  • Aw D, Silva AB, Palmer DB (2007) Immunosenescence: emerging challenges for an ageing population. Immunology 120(4):435–446

    Article  PubMed  CAS  Google Scholar 

  • Aw D, Silva AB, Maddick M, von Zglinicki T, Palmer DB (2008) Architectural changes in the thymus of aging mice. Aging Cell 7(2):158–167

    Article  PubMed  CAS  Google Scholar 

  • Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5(6):493–506

    Article  PubMed  CAS  Google Scholar 

  • Bisht K, Wagner KH, Bulmer AC (2009) Curcumin, resveratrol and flavonoids as anti-inflammatory, cyto- and DNA-protective dietary compounds. Toxicology. doi:10.1016/j.tox.2009.11.008

  • Bonafe M, Valensin S, Gianni W, Marigliano V, Franceschi C (2001) The unexpected contribution of immunosenescence to the leveling off of cancer incidence and mortality in the oldest old. Crit Rev Oncol Hematol 39(3):227–233

    Article  PubMed  CAS  Google Scholar 

  • Bruunsgaard H (2002) Effects of tumor necrosis factor-alpha and interleukin-6 in elderly populations. Eur Cytokine Netw 13(4):389–391

    PubMed  CAS  Google Scholar 

  • Bruunsgaard H, Pedersen BK (2003) Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am 23(1):15–39

    Article  PubMed  Google Scholar 

  • Burns EA, Goodwin JS (1997) Immunodeficiency of aging. Drugs Aging 11(5):374–397

    Article  PubMed  CAS  Google Scholar 

  • Callahan JE, Kappler JW, Marrack P (1993) Unexpected expansions of CD8-bearing cells in old mice. J Immunol 151(12):6657–6669

    PubMed  CAS  Google Scholar 

  • Castle SC (2000) Clinical relevance of age-related immune dysfunction. Clin Infect Dis 31(2):578–585

    Article  PubMed  CAS  Google Scholar 

  • Castle S, Uyemura K, Wong W, Modlin R, Effros R (1997) Evidence of enhanced type 2 immune response and impaired upregulation of a type 1 response in frail elderly nursing home residents. Mech Ageing Dev 94(1–3):7–16

    Article  PubMed  CAS  Google Scholar 

  • Castle SC, Uyemura K, Crawford W, Wong W, Klaustermeyer WB, Makinodan T (1999) Age-related impaired proliferation of peripheral blood mononuclear cells is associated with an increase in both IL-10 and IL-12. Exp Gerontol 34(2):243–252

    Article  PubMed  CAS  Google Scholar 

  • Chen J, Astle CM, Harrison DE (1998) Delayed immune aging in diet-restricted B6CBAT6 F1 mice is associated with preservation of naive T cells. J Gerontol A Biol Sci Med Sci 53(5):B330–B337, discussion B338-9

    Article  PubMed  CAS  Google Scholar 

  • Collins DP, Luebering BJ, Shaut DM (1998) T-lymphocyte functionality assessed by analysis of cytokine receptor expression, intracellular cytokine expression, and femtomolar detection of cytokine secretion by quantitative flow cytometry. Cytometry 33(2):249–255

    Article  PubMed  CAS  Google Scholar 

  • Das S, Das DK (2007) Anti-inflammatory responses of resveratrol. Inflamm Allergy Drug Targets 6(3):168–173

    Article  PubMed  CAS  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(26):3003–3026

    Article  PubMed  Google Scholar 

  • Dejaco C, Duftner C, Schirmer M (2006) Are regulatory T-cells linked with aging? Exp Gerontol 41(4):339–345

    Article  PubMed  CAS  Google Scholar 

  • Erol A (2007) Interleukin-6 (IL-6) is still the leading biomarker of the metabolic and aging-related disorders. Med Hypotheses 69(3):708

    Article  PubMed  CAS  Google Scholar 

  • Fagiolo U, Cossarizza A, Scala E, Fanales-Belasio E, Ortolani C, Cozzi E, Monti D, Franceschi C, Paganelli R (1993) Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol 23(9):2375–2378

    Article  PubMed  CAS  Google Scholar 

  • Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6(11):1142–1151

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Franceschi C, Valensin S, Bonafe M, Paolisso G, Yashin AI, Monti D, De Benedictis G (2000b) The network and the remodeling theories of aging: historical background and new perspectives. Exp Gerontol 35(6–7):879–896

    Article  PubMed  CAS  Google Scholar 

  • Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128(1):92–105

    Article  PubMed  CAS  Google Scholar 

  • Gabriel P, Cakman I, Rink L (2002) Overproduction of monokines by leukocytes after stimulation with lipopolysaccharide in the elderly. Exp Gerontol 37(2–3):235–247

    Article  PubMed  CAS  Google Scholar 

  • Gao X, Xu YX, Janakiraman N, Chapman RA, Gautam SC (2001) Immunomodulatory activity of resveratrol: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production. Biochem Pharmacol 62(9):1299–1308

    Article  PubMed  CAS  Google Scholar 

  • Gedik CM, Collins A (2005) Establishing the background level of base oxidation in human lymphocyte DNA: results of an interlaboratory validation study. Faseb J 19(1):82–84

    PubMed  CAS  Google Scholar 

  • Globerson A, Effros RB (2000) Ageing of lymphocytes and lymphocytes in the aged. Immunol Today 21(10):515–521

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Quintial R, Theofilopoulos AN (1992) V beta gene repertoires in aging mice. J Immunol 149(1):230–236

    PubMed  CAS  Google Scholar 

  • Gregg R, Smith CM, Clark FJ, Dunnion D, Khan N, Chakraverty R, Nayak L, Moss PA (2005) The number of human peripheral blood CD4+ CD25high regulatory T cells increases with age. Clin Exp Immunol 140(3):540–546

    Article  PubMed  CAS  Google Scholar 

  • Grossmann A, Maggio-Price L, Jinneman JC, Rabinovitch PS (1991) Influence of aging on intracellular free calcium and proliferation of mouse T-cell subsets from various lymphoid organs. Cell Immunol 135(1):118–131

    Article  PubMed  CAS  Google Scholar 

  • Han GM, Zhao B, Jeyaseelan S, Feng JM (2009) Age-associated parallel increase of Foxp3(+)CD4(+) regulatory and CD44(+)CD4(+) memory T cells in SJL/J mice. Cell Immunol 258(2):188–196

    Article  PubMed  CAS  Google Scholar 

  • Hannet I, Erkeller-Yuksel F, Lydyard P, Deneys V, DeBruyere M (1992) Developmental and maturational changes in human blood lymphocyte subpopulations. Immunol Today 13(6):215–218

    Article  PubMed  CAS  Google Scholar 

  • Harper JM, Galecki AT, Burke DT, Miller RA (2004) Body weight, hormones and T cell subsets as predictors of life span in genetically heterogeneous mice. Mech Ageing Dev 125(5):381–390

    Article  PubMed  CAS  Google Scholar 

  • Horwitz DA, Zheng SG, Wang J, Gray JD (2008) The real role of TGF-beta in regulatory T cells physiology. Eur J Immunol 38(11):901–937

    Google Scholar 

  • Huang H, Patel DD, Manton KG (2005) The immune system in aging: roles of cytokines, T cells and NK cells. Front Biosci 10:192–215

    Article  PubMed  CAS  Google Scholar 

  • Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C, Malarkey WB, Glaser R (2003) Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc Natl Acad Sci USA 100(15):9090–9095

    Article  PubMed  CAS  Google Scholar 

  • Kirschmann DA, Murasko DM (1992) Splenic and inguinal lymph node T cells of aged mice respond differently to polyclonal and antigen-specific stimuli. Cell Immunol 139(2):426–437

    Article  PubMed  CAS  Google Scholar 

  • Komuro T, Sano K, Asano Y, Tada T (1990) Analysis of age-related degeneracy of T-cell repertoire: localized functional failure in CD8+ T cells. Scand J Immunol 32(5):545–553

    Article  PubMed  CAS  Google Scholar 

  • Kowalski J, Samojedny A, Paul M, Pietsz G, Wilczok T (2005) Effect of apigenin, kaempferol and resveratrol on the expression of interleukin-1beta and tumor necrosis factor-alpha genes in J774.2 macrophages. Pharmacol Rep 57(3):390–394

    PubMed  CAS  Google Scholar 

  • Krabbe KS, Pedersen M, Bruunsgaard H (2004) Inflammatory mediators in the elderly. Exp Gerontol 39(5):687–699

    Article  PubMed  CAS  Google Scholar 

  • Kulinsky VI (2007) Biochemical aspects of inflammation. Biochemistry (Mosc) 72(6):595–607

    Article  CAS  Google Scholar 

  • Li DH, Winslow MM, Cao TM, Chen AH, Davis CR, Mellins ED, Utz PJ, Crabtree GR, Parnes JR (2008) Modulation of peripheral B cell tolerance by CD72 in a murine model. Arthritis Rheum 58(10):3192–3204

    Article  PubMed  CAS  Google Scholar 

  • Linton PJ, Haynes L, Klinman NR, Swain SL (1996) Antigen-independent changes in naive CD4 T cells with aging. J Exp Med 184(5):1891–1900

    Article  PubMed  CAS  Google Scholar 

  • Manna SK, Mukhopadhyay A, Aggarwal BB (2000) Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol 164(12):6509–6519

    PubMed  CAS  Google Scholar 

  • McElhaney JE, Effros RB (2009) Immunosenescence: what does it mean to health outcomes in older adults? Curr Opin Immunol 21(4):418–424

    Article  PubMed  CAS  Google Scholar 

  • Miller RA (1996) The aging immune system: primer and prospectus. Science 273(5271):70–74

    Article  PubMed  CAS  Google Scholar 

  • Miller RA (1997) Age-related changes in T cell surface markers: a longitudinal analysis in genetically heterogeneous mice. Mech Ageing Dev 96(1–3):181–196

    Article  PubMed  CAS  Google Scholar 

  • Miller RA (2001) Biomarkers of aging: prediction of longevity by using age-sensitive T-cell subset determinations in a middle-aged, genetically heterogeneous mouse population. J Gerontol A Biol Sci Med Sci 56(4):B180–B186

    Article  PubMed  CAS  Google Scholar 

  • Miller JF (2002) The discovery of thymus function and of thymus-derived lymphocytes. Immunol Rev 185:7–14

    Article  PubMed  CAS  Google Scholar 

  • Nagel JE, Chopra RK, Chrest FJ, McCoy MT, Schneider EL, Holbrook NJ, Adler WH (1988) Decreased proliferation, interleukin 2 synthesis, and interleukin 2 receptor expression are accompanied by decreased mRNA expression in phytohemagglutinin-stimulated cells from elderly donors. J Clin Invest 81(4):1096–1102

    Article  PubMed  CAS  Google Scholar 

  • Nikolich-Zugich J, Messaoudi I (2005) Mice and flies and monkeys too: caloric restriction rejuvenates the aging immune system of non-human primates. Exp Gerontol 40(11):884–893

    Article  PubMed  CAS  Google Scholar 

  • Ostan R, Bucci L, Capri M, Salvioli S, Scurti M, Pini E, Monti D, Franceschi C (2008) Immunosenescence and immunogenetics of human longevity. Neuroimmunomodulation 15(4–6):224–240

    Article  PubMed  CAS  Google Scholar 

  • Pahlavani MA (2004) Influence of caloric restriction on aging immune system. J Nutr Health Aging 8(1):38–47

    PubMed  CAS  Google Scholar 

  • Park SK, Kim K, Page GP, Allison DB, Weindruch R, Prolla TA (2009) Gene expression profiling of aging in multiple mouse strains: identification of aging biomarkers and impact of dietary antioxidants. Aging Cell 8(4):484–495

    Article  PubMed  CAS  Google Scholar 

  • Pawelec G (1999) Immunosenescence: impact in the young as well as the old? Mech Ageing Dev 108(1):1–7

    Article  PubMed  CAS  Google Scholar 

  • Pawelec G, Barnett Y, Forsey R, Frasca D, Globerson A, McLeod J, Caruso C, Franceschi C, Fulop T, Gupta S, Mariani E, Mocchegiani E, Solana R (2002) T cells and aging, January 2002 update. Front Biosci 7:d1056–d1183

    PubMed  CAS  Google Scholar 

  • Pawelec G, Akbar A, Caruso C, Solana R, Grubeck-Loebenstein B, Wikby A (2005) Human immunosenescence: is it infectious? Immunol Rev 205:257–268

    Article  PubMed  CAS  Google Scholar 

  • Pervaiz S, Holme AL, Aggarwal BB, Anekonda TS, Baur JA, Gojkovic-Bukarica L, Ragione FD, Kim AL, Pirola L, Saiko P (2009) Resveratrol: its biologic targets and functional activity. Antioxid Redox Signal 11(11):2851–2897

    Article  PubMed  CAS  Google Scholar 

  • Pfister G, Weiskopf D, Lazuardi L, Kovaiou RD, Cioca DP, Keller M, Lorbeg B, Parson W, Grubeck-Loebenstein B (2006) Naive T cells in the elderly: are they still there? Ann NY Acad Sci 1067:152–157

    Article  PubMed  CAS  Google Scholar 

  • Rink L, Cakman I, Kirchner H (1998) Altered cytokine production in the elderly. Mech Ageing Dev 102(2–3):199–209

    Article  PubMed  CAS  Google Scholar 

  • Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, Shimizu J, Takahashi T, Nomura T (2006) Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 212:8–27

    Article  PubMed  CAS  Google Scholar 

  • Sander M, Avlund K, Lauritzen M, Gottlieb T, Halliwell B, Stevnsner T, Wewer U, Bohr VA (2008) Aging-from molecules to populations. Mech Ageing Dev 129(10):614–623

    Article  PubMed  Google Scholar 

  • Sansoni P, Vescovini R, Fagnoni F, Biasini C, Zanni F, Zanlari L, Telera A, Lucchini G, Passeri G, Monti D, Franceschi C, Passeri M (2007) The immune system in extreme longevity. Exp Gerontol 43(2):61–65

    Article  PubMed  Google Scholar 

  • Saule P, Trauet J, Dutriez V, Lekeux V, Dessaint JP, Labalette M (2006) Accumulation of memory T cells from childhood to old age: central and effector memory cells in CD4(+) versus effector memory and terminally differentiated memory cells in CD8(+) compartment. Mech Ageing Dev 127(3):274–281

    Article  PubMed  CAS  Google Scholar 

  • Sharma S, Dominguez AL, Lustgarten J (2006) High accumulation of T regulatory cells prevents the activation of immune responses in aged animals. J Immunol 177(12):8348–8355

    PubMed  CAS  Google Scholar 

  • Taub DD, Longo DL (2005) Insights into thymic aging and regeneration. Immunol Rev 205:72–93

    Article  PubMed  CAS  Google Scholar 

  • Valavanidis A, Vlachogianni T, Fiotakis C (2009) 8-hydroxy-2′ -deoxyguanosine (8-OHdG): a critical biomarker of oxidative stress and carcinogenesis. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 27(2):120–139

    PubMed  CAS  Google Scholar 

  • Walford RL (1982) Studies in immunogerontology. J Am Geriatr Soc 30(10):617–625

    PubMed  CAS  Google Scholar 

  • Weiskopf D, Weinberger B, Grubeck-Loebenstein B (2009) The aging of the immune system. Transpl Int 22(11):1041–1050

    Article  PubMed  CAS  Google Scholar 

  • Witkowski JM, Miller RA (1993) Increased function of P-glycoprotein in T lymphocyte subsets of aging mice. J Immunol 150(4):1296–1306

    PubMed  CAS  Google Scholar 

  • Wong YT, Gruber J, Jenner AM, Ng MP, Ruan R, Tay FE (2009) Elevation of oxidative-damage biomarkers during aging in F2 hybrid mice: protection by chronic oral intake of resveratrol. Free Radic Biol Med 46(6):799–809

    Article  PubMed  CAS  Google Scholar 

  • Wu HJ, Bondada S (2009) CD72, a coreceptor with both positive and negative effects on B lymphocyte development and function. J Clin Immunol 29(1):12–21

    Article  PubMed  CAS  Google Scholar 

  • Wu LL, Chiou CC, Chang PY, Wu JT (2004) Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. Clin Chim Acta 339(1–2):1–9

    Article  PubMed  CAS  Google Scholar 

  • Zhao L, Sun L, Wang H, Ma H, Liu G, Zhao Y (2007) Changes of CD4+CD25+Foxp3+ regulatory T cells in aged Balb/c mice. J Leukoc Biol 81(6):1386–1394

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was financially supported by the Institute of Bioengineering and Nanotechnology, the Agency for Science, Technology and Research (A*STAR), Singapore and the Biomedical Research Council (Project No.: 01/1/21/19/172), Singapore. We would like to acknowledge the assistance of Manickaratnam Ranjan in the gene expression analysis. We would also like to thank Dr Paul A. MacAry for his technical input on the manuscript.

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Authors and Affiliations

  1. Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, #04-01, The Nanos, Singapore, Singapore, 138669

    Yee Ting Wong & Runsheng Ruan

  2. Department of Mechanical Engineering, National University of Singapore, Singapore, Singapore

    Yee Ting Wong & Francis Eng Hock Tay

  3. Neurobiology and Ageing Programme, Department of Biochemistry, National University of Singapore, Singapore, Singapore

    Jan Gruber & Andrew M. Jenner

  4. Medical Devices Research Group, Institute of Bioengineering and Nanotechnology, Singapore, Singapore

    Francis Eng Hock Tay

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  1. Yee Ting Wong
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Correspondence to Runsheng Ruan.

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Wong, Y.T., Gruber, J., Jenner, A.M. et al. Chronic resveratrol intake reverses pro-inflammatory cytokine profile and oxidative DNA damage in ageing hybrid mice. AGE 33, 229–246 (2011). https://doi.org/10.1007/s11357-010-9174-4

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