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红景天苷的抗衰老作用:口服红景天苷改善老龄大鼠免疫反应和增强谷氨酰半胱氨酸连接酶活性
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摘要
众所周知,机体的免疫应答能力随着衰老而逐渐下降。红景天苷(Salidroside,SDS),是一种由中国传统中药红景天(Rhodiola L.)植物根茎中提取的抗氧化成分,一直以来以抗衰老,促进健康等功能而著称。然而,这种功能的内在机制却还不太明了。本研究明确证实(1)SDS口服吸收可使老龄Wistar雄性大鼠脾内CD3+T细胞和CD4+辅助性T细胞显著增加;(2)SDS能显著增强老龄大鼠体内迟发型超敏反应(DTH反应),该反应是由T细胞介导的免疫反应;(3)SDS口服吸收能在不影响体内免疫平衡的基础上,显著性增加抗KLH特异性的IgG,IgG1和IgG2α的数量。以上实验结果证明SDS具有对抗免疫衰老的作用,进而具有延年益寿的功效。因此,SDS可以被用来帮助老年个体提高对疫苗的反应,促进老年个体细胞和体液介导的免疫应答。
     谷氨酰半胱氨酸连接酶(Glutamate cysteine ligase, GCL)是谷胱甘肽(Glutathione, GSH)生物合成过程中的限速酶。许多数据显示衰老过程可能与机体内GCL水平的下降有关。本研究结果表明在老龄大鼠肝脏,心脏及脑组织中,GCL催化亚基(GCLc)和调节亚基(GCLm)基因的表达均显著下降,GCL酶活也显著降低。然而,通过口服红景天苷,则能够逆转上述状况,使老龄大鼠肝脏、心脏、脑中GCLc和GCLm基因的表达显著增加,GCL的活性显著增强,GCLC与GCLM亚基的蛋白含量也明显升高。除此之外,通过该实验结果,认为利用红景天苷进行营养干预,可有助于老年个体提高其抗氧化能力。
     综上,本实验结果表明在老龄大鼠中,红景天苷通过促进免疫应答,对抗免疫衰老,提高抗氧化能力,从而发挥其抗衰老作用。
It is well known that immune response decreases with aging. Salidroside (SDS),an antioxidant component isolated from the traditional Chinese medicine roserootRhodiola rosea, has been demonstrated to possess potent anti-aging andhealth-promoting activities. However, the mechanism underlying these activities ispoorly understood. In this study, we clearly demonstrated that (1) dietary intake ofSDS induced a considerable increase in total T cells (CD3+) and T helper cells (CD4+)in aged Wistar male rats;(2) SDS supplementation significantly increased the DTHresponse, a T cell-mediated immune response, in aged rats; and (3) SDSsupplementation remarkably promoted the production of total anti-KLH IgG,anti-KLH IgG1and anti-KLH IgG2in aged rats without disturbing immunehomeostasis. These indicate that SDS is able to counteract immunosenescence,thereby resulting in rejuvenation. Pratically, SDS may be used to help the elderly togenerate an improved response to vaccine with stronger humoral and cell-mediatedimmune responses.
     Glutamate cysteine ligase (GCL) is the rate-limiting enzyme in GSHbiosynthesis. Several lines indicate that aging process may be related to reduction inGCL in organisms. Here we demonstrated that expression of GCL catalytic subunit(GCLc) and modulatory subunit (GCLm) decreased significantly in the liver, heartand brain from aged rats (22.5-month-old), and GCL activity also declinedsignificantly in all the tissues from aged rats. Notably, the decreases in GCLc andGCLm expression, GCL activity and GCLc and GCLm contents in the livers, heartsand brains from aged rats were resersed by oral administration of salodroside, a strongantioxidant with rejuvenating activity. These data indicate that salidroside is capableof enhancing GCL activity in vivo in aged rats. It also suggests that late onsetnutritional interventions with salidroside may help elder subjects to generate an improved redox state.
引文
1.中国药典,一部[S].2005.
    2. Mell, C., Dyes, tannins, perfumes, and medicines from Rhodiola rosea. TextileColorist,1938.60(715): p.483-4.
    3. Krylov, G., Herbs for Life.1969, Novosibirsk: Academic Press.
    4. Dabrosin, C. and K. Ollinger, Variability of glutathione during the menstrualcycle-due to estrogen effects on hepatocytes? Free Radic Biol Med,2004.36(2): p.145-51.
    5. Kurkin, V. and G. Zapesochnaya, Chemical composition and pharmacologicalproperties of Rhodiola rosea. Chemical and Pharmaceutical Journal (Moscow),1986.20(10):p.1231-44.
    6. Kelly, G.S., Rhodiola rosea: a possible plant adaptogen. Altern Med Rev,2001.6(3): p.293-302.
    7. Yu, S., et al., Neuroprotective effects of salidroside in the PC12cell modelexposed to hypoglycemia and serum limitation. Cell Mol Neurobiol,2008.28(8): p.1067-78.
    8. Ye, Y.C., et al.,[Effect of salidroside on cultured myocardial cellsanoxia/reoxygenation injuries]. Zhongguo Yao Li Xue Bao,1993.14(5): p.424-6.
    9. Wang, H., et al., The in vitro and in vivo antiviral effects of salidroside fromRhodiola rosea L. against coxsackievirus B3. Phytomedicine,2009.16(2-3): p.146-55.
    10. Skopinska-Rozewska, E., et al., The influence of Rhodiola quadrifida50%hydro-alcoholic extract and salidroside on tumor-induced angiogenesis in mice. Pol J Vet Sci,
    2008.11(2): p.97-104.
    11. Liu, Z., et al., Rhodiola rosea extracts and salidroside decrease the growth ofbladder cancer cell lines via inhibition of the mTOR pathway and induction of autophagy.Mol Carcinog,2012.51(3): p.257-67.
    12. Guan, S., et al., Salidroside attenuates hydrogen peroxide-induced cell damagethrough a cAMP-dependent pathway. Molecules,2011.16(4): p.3371-9.
    13. Kanupriya, et al., Cytoprotective and antioxidant activity of Rhodiola imbricataagainst tert-butyl hydroperoxide induced oxidative injury in U-937human macrophages. MolCell Biochem,2005.275(1-2): p.1-6.
    14. Ma, L., et al.,[Protective effects of salidroside on oxidative damage in fatiguemice]. Zhong Xi Yi Jie He Xue Bao,2009.7(3): p.237-41.
    15. Mao, G.X., et al., Protective role of salidroside against aging in a mouse modelinduced by D-galactose. Biomed Environ Sci,2010.23(2): p.161-6.
    16. Wu, T., et al., Cardioprotection of salidroside from ischemia/reperfusion injury byincreasing N-acetylglucosamine linkage to cellular proteins. Eur J Pharmacol,2009.613(1-3):p.93-9.
    17. Wang, Q., et al.,[Salidroside protects the hypothalamic-pituitary-gonad axis ofmale rats undergoing negative psychological stress in experimental navigation and intensiveexercise]. Zhonghua Nan Ke Xue,2009.15(4): p.331-6.
    18. Mao, G.X., et al., Protective Role of Salidroside against Aging in A Mouse ModelInduced by D-galactose. Biomedical and Environmental Sciences,2010.23(2): p.161-166.
    19. Schriner, S.E., et al., Protection of human cultured cells against oxidative stressby Rhodiola rosea without activation of antioxidant defenses. Free Radic Biol Med,2009.47(5): p.577-84.
    20. Choi, H.G., et al., Phenolic glycosides from Lindera obtusiloba and theiranti-allergic inflammatory activities. Nat Prod Commun,2013.8(2): p.181-2.
    21. Li, D., et al., Salidroside attenuates inflammatory responses by suppressingnuclear factor-kappaB and mitogen activated protein kinases activation inlipopolysaccharide-induced mastitis in mice. Inflamm Res,2013.62(1): p.9-15.
    22. Guan, S., et al., Protective effects of salidroside from Rhodiola rosea onLPS-induced acute lung injury in mice. Immunopharmacol Immunotoxicol,2012.34(4): p.667-72.
    23. Yuan, Y., et al., Dimeric Sfh3has structural changes in its binding pocket that areassociated with a dimer-monomer state transformation induced by substrate binding. ActaCrystallogr D Biol Crystallogr,2013.69(Pt3): p.313-23.
    24. Zhang, J.K., et al., Protection by Salidroside against Bone Loss via Inhibition ofOxidative Stress and Bone-Resorbing Mediators. PLoS One,2013.8(2): p. e57251.
    25. Zhang, J., et al., Salidroside attenuates beta amyloid-induced cognitive deficits viamodulating oxidative stress and inflammatory mediators in rat hippocampus. Behav Brain Res,
    2013.244: p.70-81.
    26. Xu, J.F., et al., Statins and pulmonary fibrosis: the potential role of NLRP3inflammasome activation. Am J Respir Crit Care Med,2012.185(5): p.547-56.
    27. Zotova, M., The effect of Rhodiola rosea extract on mental working activity inman. In Collection of Reports at3rd Scientific Conference of Physiologists, Biochemists andPharmacologists of WesternSiberia, Tomsk,1965: p.298-299.
    28. Shevtsov, V., et al., A randomized trial of two different doses of a SHR-5Rhodiola rosea extract versus placebo and control of capacity for mental work.Phytomedicine,2003.10(2): p.95-105.
    29. Krasik, E., et al., Therapy of asthenic conditions: clinical perspectives ofapplication of Rhodiola rosea extract (golden root). Proceedings of Modern Problems inPsychopharmacology. Kemerovo, Russia: Siberian Branch of the Russian Academy ofSciences,1970.
    30. De Bock, K., et al., Acute Rhodiola rosea intake can improve endurance exerciseperformance. Int J Sport Nutr Exerc Metab,2004.14(3): p.298-307.
    31. Perfumi, M. and L. Mattioli, Adaptogenic and central nervous system effects ofsingle doses of3%rosavin and1%salidroside Rhodiola rosea L. extract in mice. PhytotherRes,2007.21(1): p.37-43.
    32. Panossian, A., et al., Comparative study of Rhodiola preparations on behavioraldespair of rats. Phytomedicine,2008.15(1-2): p.84-91.
    33. Petkov, V.D., et al., Effects of alcohol aqueous extract from Rhodiola rosea L.roots on learning and memory. Acta Physiol Pharmacol Bulg,1986.12(1): p.3-16.
    34. Kurkin V A, D.A.V., Ezhkov V N,et al., Nootropic activity of somephytopreparations and phenylpropanoids. Rastit Resur,2007.43(2): p.76-88.
    35. Battistelli, M., et al., Rhodiola rosea as antioxidant in red blood cells:ultrastructural and hemolytic behaviour. Eur J Histochem,2005.49(3): p.243-54.
    36. Kim, S.H., S.H. Hyun, and S.Y. Choung, Antioxidative effects of Cinnamomicassiae and Rhodiola rosea extracts in liver of diabetic mice. Biofactors,2006.26(3): p.209-219.
    37. Molokovsky, D., V. Davydov, and V. Tyulenev, Effect of AdaptogenicPhytopharmaceuticals in Experimental Alloxan Diabetes. Preblemy Endokronologii,1989.35:p.82-87.
    38. Salikhova, R.A., et al.,[Effect of Rhodiola rosea on the yield of mutationalterations and DNA repair in bone marrow cells]. Patol Fiziol Eksp Ter,1997(4): p.22-4.
    39. Bocharova, O.A., et al.,[The effect of a Rhodiola rosea extract on the incidence ofrecurrences of a superficial bladder cancer (experimental clinical research)]. Urol Nefrol(Mosk),1995(2): p.46-7.
    40. Udintsev S N, K.S.G., Fomina T I, On the potentiating effect of hepatoprotectorsof plant origin on adriamycin administered for liver metastases from Ehrlich adenocarcinomain mice. Vopr Onkol,1992.38(12): p.1217-1222.
    41. Majewska, A., et al., Antiproliferative and antimitotic effect, S phaseaccumulation and induction of apoptosis and necrosis after treatment of extract fromRhodiola rosea rhizomes on HL-60cells. J Ethnopharmacol,2006.103(1): p.43-52.
    42. Iaremi, I. and N. Grigor'eva,[Hepatoprotective properties of liquid extract ofRhodiola rosea]. Eksperimental'naia i klinicheskaia farmakologiia,2002.65(6): p.57.
    43. Lishmanov Iu, B., et al.,[The anti-arrhythmia effect of Rhodiola rosea and itspossible mechanism]. Biull Eksp Biol Med,1993.116(8): p.175-6.
    44. Lishmanov Iu, B., et al.,[Contribution of the opioid system to realization ofinotropic effects of Rhodiola rosea extracts in ischemic and reperfusion heart damage invitro]. Eksp Klin Farmakol,1997.60(3): p.34-6.
    45. Maslov, L.N. and B. Lishmanov Iu,[Cardioprotective and antiarrhythmicproperties of Rhodiolae roseae preparations]. Eksp Klin Farmakol,2007.70(5): p.59-67.
    46. Gerasimova, H.D., Effect of Rhodiola rosea extract on ovarian functional activity.Proc. of Scientific Conference on Endocrinology and Gynecology. Sverdlovk, Russia,1970: p.46-48.
    47. Saratikov A S, K.E.A., The influence of Rhodiola on endocrine glands and theliver:[Rhodiolarosea is a valuable medicinal plant (Golden Root)]. Tomsk:Tomsk State University,1987: p.180-193.
    48. Kurkin, V. and G. Zapesochnaya, Chemical composition and pharmacologicalcharacteristics of Rhodiola rosea. Journal of Medicinal Plants, Russian Academy of Science,Moscow,1985: p.1231-445.
    49. Udintsev, S.N. and V.P. Schakhov, Decrease of cyclophosphamidehaematotoxicity by Rhodiola rosea root extract in mice with Ehrlich and Lewis transplantabletumors. European journal of cancer (Oxford, England:1990),1991.27(9): p.1182.
    50.马朝阳,玫瑰红景天有效成分分离纯化及结构鉴定.2009,江南大学.
    51.孙晓生and杨柳,抗衰老机制与药物的研究进展.广州中医药大学学报,
    2009.26(6): p.593-7.
    52.毕明刚,胸腺淋巴细胞分化与Notch信号转导通路的关系及六味地黄汤的作用研究.中国人民解放军军事医学科学院,2004.
    53. Walford, R.L., Auto-immunity and aging. J Gerontol,1962.17: p.281-5.
    54. Walford, R.L., Immunologic theory of aging: current status. Fed Proc,1974.33(9):p.2020-7.
    55. Henriksen, F.W. and S. Hancke, Percutaneous cystogastrostomy for chronicpancreatic pseudocyst. Br J Surg,1994.81(10): p.1525-8.
    56. Holmes, G.E., C. Bernstein, and H. Bernstein, Oxidative and other DNA damagesas the basis of aging: a review. Mutat Res,1992.275(3-6): p.305-15.
    57. Chelvarajan, R.L., et al., Molecular basis of age-associated cytokine dysregulationin LPS-stimulated macrophages. J Leukoc Biol,2006.79(6): p.1314-27.
    58. Meydani, S.N., et al., Antioxidants and immune response in aged persons:overview of present evidence. Am J Clin Nutr,1995.62(6Suppl): p.1462S-1476S.
    59. Lesourd, B.M. and S. Meaume, Cell mediated immunity changes in ageing,relative importance of cell subpopulation switches and of nutritional factors. Immunol Lett,
    1994.40(3): p.235-42.
    60. Negoro, S., et al., Mechanisms of age-related decline in antigen-specific T cellproliferative response: IL-2receptor expression and recombinant IL-2induced proliferativeresponse of purified Tac-positive T cells. Mech Ageing Dev,1986.36(3): p.223-41.
    61. Ginaldi, L., et al., The immune system in the elderly: III. Innate immunity.Immunol Res,1999.20(2): p.117-26.
    62.徐济民,老年人T细胞及亚群变化的初步探讨.中华老年医学杂志,1982.1:p.9-12.
    63.单颖, et al.,老年人T细胞亚群的Meta分析.中国老年学杂志,2007.19(10): p.1905-1907.
    64. Messaoudi, I., et al., Age-related CD8T cell clonal expansions constrict CD8Tcell repertoire and have the potential to impair immune defense. J Exp Med,2004.200(10): p.1347-58.
    65. Sansoni, P., et al., Lymphocyte subsets and natural killer cell activity in healthyold people and centenarians. Blood,1993.82(9): p.2767-73.
    66.刘学员,卢水焕, and唐慧明,老年患者淋巴细胞亚群及其相关因素分析[J].中国实用内科杂志,2008.28(1): p.100-102.
    67.吴迎星,谭家余, and吴赛珠,老年人T淋巴细胞亚群的变化规律.中华实用医学,2002.22(4): p.9-9.
    68.马聪and向丹,老年及老年前期正常人外周血T淋巴细胞亚群变化的研究.中国老年学杂志,1995.15(1): p.30-32.
    69. Tomoiu, A., et al., Do membrane rafts contribute to human immunosenescence?Ann N Y Acad Sci,2007.1100: p.98-110.
    70.杜星琼,黄翠, and边艳青,衰老与适应性免疫.医学信息:上旬刊,2011.24(11): p.3487-3488.
    71. Zhao, B.L., S.J. Duan, and W.J. Xin, Lymphocytes can produce respiratory burstand oxygen radicals as polymorphonuclear leukocytes. Cell Biophys,1990.17(3): p.205-11.
    72. Grever, M.R., et al., The effect of oxidant stress on human lymphocyte cytotoxicity.Blood,1980.56(2): p.284-8.
    73. Miller, J.P. and D. Allman, The decline in B lymphopoiesis in aged mice reflectsloss of very early B-lineage precursors. J Immunol,2003.171(5): p.2326-30.
    74. Lu, L., P. Chaudhury, and D.G. Osmond, Regulation of cell survival during Blymphopoiesis: apoptosis and Bcl-2/Bax content of precursor B cells in bone marrow of micewith altered expression of IL-7and recombinase-activating gene-2. J Immunol,1999.162(4):p.1931-40.
    75. Weinberger, B., et al., Biology of immune responses to vaccines in elderly persons.Clin Infect Dis,2008.46(7): p.1078-84.
    76.张李峰,红芪和黄芪的免疫调节作用及抗免疫老化机制比较研究.2012,兰州大学.
    77. Chambers, S.M., et al., Aging hematopoietic stem cells decline in function andexhibit epigenetic dysregulation. PLoS Biol,2007.5(8): p. e201.
    78. de Haan, G., W. Nijhof, and G. Van Zant, Mouse strain-dependent changes infrequency and proliferation of hematopoietic stem cells during aging: correlation betweenlifespan and cycling activity. Blood,1997.89(5): p.1543-50.
    79. Hotta, T., et al., Age-related changes in the function of hemopoietic stroma in mice.Exp Hematol,1980.8(7): p.933-6.
    80. Rossi, D.J., et al., Cell intrinsic alterations underlie hematopoietic stem cell aging.Proc Natl Acad Sci U S A,2005.102(26): p.9194-9.
    81. Sudo, K., et al., Age-associated characteristics of murine hematopoietic stem cells.J Exp Med,2000.192(9): p.1273-80.
    82. Muller-Sieburg, C.E. and R. Riblet, Genetic control of the frequency ofhematopoietic stem cells in mice: mapping of a candidate locus to chromosome1. J Exp Med,
    1996.183(3): p.1141-50.
    83. Phillips, R.L., A.J. Reinhart, and G. Van Zant, Genetic control of murinehematopoietic stem cell pool sizes and cycling kinetics. Proc Natl Acad Sci U S A,1992.89(23): p.11607-11.
    84. Kuranda, K., et al., Age-related changes in human hematopoietic stem/progenitorcells. Aging Cell,2011.10(3): p.542-6.
    85. Tuljapurkar, S.R., et al., Changes in human bone marrow fat content associatedwith changes in hematopoietic stem cell numbers and cytokine levels with aging. J Anat,2011.219(5): p.574-81.
    86. Morrison, S.J., et al., The aging of hematopoietic stem cells. Nat Med,1996.2(9):p.1011-6.
    87. Chen, C.N., et al., Aging impairs the expression of the catalytic subunit ofglutamate cysteine ligase in soleus muscle under stress. J Gerontol A Biol Sci Med Sci,2010.65(2): p.129-37.
    88. Harrison, D.E., Long-term erythropoietic repopulating ability of old, young, andfetal stem cells. J Exp Med,1983.157(5): p.1496-504.
    89. Johnson, K.M., K. Owen, and P.L. Witte, Aging and developmental transitions inthe B cell lineage. Int Immunol,2002.14(11): p.1313-23.
    90. Labrie, J.E.,3rd, et al., Bone marrow microenvironmental changes underliereduced RAG-mediated recombination and B cell generation in aged mice. J Exp Med,2004.200(4): p.411-23.
    91. Min, H., E. Montecino-Rodriguez, and K. Dorshkind, Reassessing the role ofgrowth hormone and sex steroids in thymic involution. Clin Immunol,2006.118(1): p.117-23.
    92. Barber, C.L., E. Montecino-Rodriguez, and K. Dorshkind, Reduced production ofB-1-specified common lymphoid progenitors results in diminished potential of adult marrowto generate B-1cells. Proc Natl Acad Sci U S A,2011.108(33): p.13700-4.
    93. Kline, G.H., T.A. Hayden, and N.R. Klinman, B cell maintenance in aged micereflects both increased B cell longevity and decreased B cell generation. J Immunol,1999.162(6): p.3342-9.
    94. Min, H., E. Montecino-Rodriguez, and K. Dorshkind, Effects of aging on thecommon lymphoid progenitor to pro-B cell transition. J Immunol,2006.176(2): p.1007-12.
    95. Rossi, D.J., et al., Deficiencies in DNA damage repair limit the function ofhaematopoietic stem cells with age. Nature,2007.447(7145): p.725-9.
    96. Tothova, Z., et al., FoxOs are critical mediators of hematopoietic stem cellresistance to physiologic oxidative stress. Cell,2007.128(2): p.325-39.
    97. Shipounova, I.N., et al., Reactive oxygen species produced in mitochondria areinvolved in age-dependent changes of hematopoietic and mesenchymal progenitor cells inmice. A study with the novel mitochondria-targeted antioxidant SkQ1. Mech Ageing Dev,
    2010.131(6): p.415-21.
    98. Jang, Y.Y. and S.J. Sharkis, A low level of reactive oxygen species selects forprimitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood,2007.110(8): p.3056-63.
    99. French, R.A., et al., Age-associated loss of bone marrow hematopoietic cells isreversed by GH and accompanies thymic reconstitution. Endocrinology,2002.143(2): p.690-9.
    100. Kucia, M., et al., Reduced number of VSELs in the bone marrow of growthhormone transgenic mice indicates that chronically elevated Igf1level acceleratesage-dependent exhaustion of pluripotent stem cell pool: a novel view on aging. Leukemia,
    2011.25(8): p.1370-4.
    101. Chinn, I.K., et al., Changes in primary lymphoid organs with aging. SeminImmunol,2012.24(5): p.309-20.
    102. Sempowski, G.D., et al., Leukemia inhibitory factor, oncostatin M, IL-6, and stemcell factor mRNA expression in human thymus increases with age and is associated withthymic atrophy. J Immunol,2000.164(4): p.2180-7.
    103. Rosen, P., Aging of the immune system. Med Hypotheses,1985.18(2): p.157-61.
    104.毛海兵,胸腺的结构及生理作用.生物学通报,1994.29(4): p.16-17.
    105.陈海英,孔月红, and蔡兆明,大鼠胸腺增龄变化的形态学研究.医学理论与实践,2005.18(2).
    106. Min, H., E. Montecino-Rodriguez, and K. Dorshkind, Reduction in thedevelopmental potential of intrathymic T cell progenitors with age. J Immunol,2004.173(1):p.245-50.
    107. Taub, D.D. and D.L. Longo, Insights into thymic aging and regeneration.Immunol Rev,2005.205: p.72-93.
    108. Zhu, M. and Y.X. Fu, Coordinating development of medullary thymic epithelialcells. Immunity,2008.29(3): p.386-8.
    109. Montecino-Rodriquez, E., H. Min, and K. Dorshkind, Reevaluating currentmodels of thymic involution. Semin Immunol,2005.17(5): p.356-61.
    110. Mackall, C.L., et al., Thymic function in young/old chimeras: substantial thymic Tcell regenerative capacity despite irreversible age-associated thymic involution. Eur JImmunol,1998.28(6): p.1886-93.
    111. Zhu, X., et al., Lymphohematopoietic progenitors do not have a synchronizeddefect with age-related thymic involution. Aging Cell,2007.6(5): p.663-72.
    112. Klug, D.B., et al., Transgenic expression of cyclin D1in thymic epithelialprecursors promotes epithelial and T cell development. J Immunol,2000.164(4): p.1881-8.
    113. Nowell, C.S., et al., Foxn1regulates lineage progression in cortical andmedullary thymic epithelial cells but is dispensable for medullary sublineage divergence.PLoS Genet,2011.7(11): p. e1002348.
    114. Sempowski, G.D., et al., Leukemia inhibitory factor is a mediator of Escherichiacoli lipopolysaccharide-induced acute thymic atrophy. Eur J Immunol,2002.32(11): p.3066-70.
    115. Billard, M.J., A.L. Gruver, and G.D. Sempowski, Acute endotoxin-induced thymicatrophy is characterized by intrathymic inflammatory and wound healing responses. PLoSOne,2011.6(3): p. e17940.
    116. Kaestner, K.H., W. Knochel, and D.E. Martinez, Unified nomenclature for thewinged helix/forkhead transcription factors. Genes Dev,2000.14(2): p.142-6.
    117. Nehls, M., et al., Two genetically separable steps in the differentiation of thymicepithelium. Science,1996.272(5263): p.886-9.
    118. Chen, L., S. Xiao, and N.R. Manley, Foxn1is required to maintain the postnatalthymic microenvironment in a dosage-sensitive manner. Blood,2009.113(3): p.567-74.
    119. Ortman, C.L., et al., Molecular characterization of the mouse involuted thymus:aberrations in expression of transcription regulators in thymocyte and epithelialcompartments. Int Immunol,2002.14(7): p.813-22.
    120. Zook, E.C., et al., Overexpression of Foxn1attenuates age-associated thymicinvolution and prevents the expansion of peripheral CD4memory T cells. Blood,2011.118(22): p.5723-31.
    121. Revest, J.M., et al., Development of the thymus requires signaling through thefibroblast growth factor receptor R2-IIIb. J Immunol,2001.167(4): p.1954-61.
    122. Erickson, M., et al., Regulation of thymic epithelium by keratinocyte growth factor.Blood,2002.100(9): p.3269-78.
    123. Caruso, C., et al., Aging, longevity, inflammation, and cancer. Ann N Y Acad Sci,
    2004.1028: p.1-13.
    124. Chung, H.Y., et al., Molecular inflammation: underpinnings of aging andage-related diseases. Ageing Res Rev,2009.8(1): p.18-30.
    125. Sarkar, D. and P.B. Fisher, Molecular mechanisms of aging-associatedinflammation. Cancer Lett,2006.236(1): p.13-23.
    126. Adamson, R., Role of macrophages in normal wound healing: an overview. JWound Care,2009.18(8): p.349-51.
    127. Gordon, S., The macrophage: past, present and future. Eur J Immunol,2007.37Suppl1: p. S9-17.
    128. Mantovani, A., et al., The chemokine system in diverse forms of macrophageactivation and polarization. Trends Immunol,2004.25(12): p.677-86.
    129. Gomez, C.R., et al., Serum from aged F344rats conditions the activation of youngmacrophages. Mech Ageing Dev,2006.127(3): p.257-63.
    130. Wang, C.Q., et al., Effect of age on marrow macrophage number and function.Aging (Milano),1995.7(5): p.379-84.
    131. Vandanmagsar, B., et al., The NLRP3inflammasome instigates obesity-inducedinflammation and insulin resistance. Nat Med,2011.17(2): p.179-88.
    132. Tasat, D.R., et al., Age-dependent change in reactive oxygen species and nitricoxide generation by rat alveolar macrophages. Aging Cell,2003.2(3): p.159-64.
    133. Shaik-Dasthagirisaheb, Y.B., A. Kantarci, and F.C. Gibson,3rd, Immune responseof macrophages from young and aged mice to the oral pathogenic bacterium Porphyromonasgingivalis. Immun Ageing,2010.7: p.15.
    134. Kovacs, E.J., T.P. Plackett, and P.L. Witte, Estrogen replacement, aging, andcell-mediated immunity after injury. J Leukoc Biol,2004.76(1): p.36-41.
    135. Murciano, C., et al., Impaired immune response to Candida albicans in aged mice.J Med Microbiol,2006.55(Pt12): p.1649-56.
    136. Kawai, T. and S. Akira, TLR signaling. Cell Death Differ,2006.13(5): p.816-25.
    137. Kong, K.F., et al., Dysregulation of TLR3impairs the innate immune response toWest Nile virus in the elderly. J Virol,2008.82(15): p.7613-23.
    138. Takeuchi, O., K. Hoshino, and S. Akira, Cutting edge: TLR2-deficient andMyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J Immunol,
    2000.165(10): p.5392-6.
    139. Gong, J., et al., Inhibition of Toll-like receptors TLR4and7signaling pathways bySIGIRR: a computational approach. J Struct Biol,2010.169(3): p.323-30.
    140. Gerlis, L.M., Bizarre presentation and long survival after a gunshot woundinvolving the heart. Int J Cardiol,2006.108(3): p.408-9.
    141. Kelly, J., et al., Senescence regulates macrophage activation and angiogenic fateat sites of tissue injury in mice. J Clin Invest,2007.117(11): p.3421-6.
    142. Sebastian, C., et al., Telomere shortening and oxidative stress in agedmacrophages results in impaired STAT5a phosphorylation. J Immunol,2009.183(4): p.2356-64.
    143. Ding, A., S. Hwang, and R. Schwab, Effect of aging on murine macrophages.Diminished response to IFN-gamma for enhanced oxidative metabolism. J Immunol,1994.153(5): p.2146-52.
    144. Yoon, P., et al., Macrophage hypo-responsiveness to interferon-gamma in agedmice is associated with impaired signaling through Jak-STAT. Mech Ageing Dev,2004.125(2): p.137-43.
    145. Solana, R. and E. Mariani, NK and NK/T cells in human senescence. Vaccine,
    2000.18(16): p.1613-20.
    146. Zhang, Y., et al., In vivo kinetics of human natural killer cells: the effects ofageing and acute and chronic viral infection. Immunology,2007.121(2): p.258-65.
    147. Mocchegiani, E., et al., NK and NKT cells in aging and longevity: role of zinc andmetallothioneins. J Clin Immunol,2009.29(4): p.416-25.
    148. Albright, J.W. and J.F. Albright, Age-associated impairment of murine naturalkiller activity. Proc Natl Acad Sci U S A,1983.80(20): p.6371-5.
    149. Levy, S.M., et al., Persistently low natural killer cell activity and circulatinglevels of plasma beta endorphin: risk factors for infectious disease. Life Sci,1991.48(2): p.107-16.
    150. Mariani, E., et al., Effect of zinc supplementation on plasma IL-6and MCP-1production and NK cell function in healthy elderly: interactive influence of+647MT1a and-174IL-6polymorphic alleles. Exp Gerontol,2008.43(5): p.462-71.
    151. Rink, L., I. Cakman, and H. Kirchner, Altered cytokine production in the elderly.Mech Ageing Dev,1998.102(2-3): p.199-209.
    152. Aspinall, R., et al., Challenges for vaccination in the elderly. Immun Ageing,
    2007.4: p.9.
    153.谢红林, et al.,衰老大鼠细胞免疫功能的变化及中药天年饮的延缓衰老作用.时珍国医国药,2007.18(10): p.2393-2394.
    154. Solana, R., G. Pawelec, and R. Tarazona, Aging and innate immunity. Immunity,
    2006.24(5): p.491-4.
    155. Maher, P., The effects of stress and aging on glutathione metabolism. Ageing ResRev,2005.4(2): p.288-314.
    156. Schafer, F.Q. and G.R. Buettner, Redox environment of the cell as viewed throughthe redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med,2001.30(11): p.1191-212.
    157. Meister, A., Selective modification of glutathione metabolism. Science,1983.220(4596): p.472-7.
    158. Klatt, P. and S. Lamas, Regulation of protein function by S-glutathiolation inresponse to oxidative and nitrosative stress. Eur J Biochem,2000.267(16): p.4928-44.
    159. Dickinson, D.A. and H.J. Forman, Glutathione in defense and signaling: lessonsfrom a small thiol. Ann N Y Acad Sci,2002.973: p.488-504.
    160. Sims, N.R., M. Nilsson, and H. Muyderman, Mitochondrial glutathione: amodulator of brain cell death. J Bioenerg Biomembr,2004.36(4): p.329-33.
    161. Muyderman, H., M. Nilsson, and N.R. Sims, Highly selective and prolongeddepletion of mitochondrial glutathione in astrocytes markedly increases sensitivity toperoxynitrite. J Neurosci,2004.24(37): p.8019-28.
    162. Fernandez-Checa, J.C., et al., Mitochondrial glutathione: importance andtransport. Semin Liver Dis,1998.18(4): p.389-401.
    163. Wild, A.C. and R.T. Mulcahy, Regulation of gamma-glutamylcysteine synthetasesubunit gene expression: insights into transcriptional control of antioxidant defenses. FreeRadic Res,2000.32(4): p.281-301.
    164. Rahman, I. and W. MacNee, Regulation of redox glutathione levels and genetranscription in lung inflammation: therapeutic approaches. Free Radic Biol Med,2000.28(9): p.1405-20.
    165. Toroser, D., et al., Mechanisms of gamma-glutamylcysteine ligase regulation.Biochim Biophys Acta,2006.1760(2): p.233-44.
    166. Huang, C.S., et al., Catalytic and regulatory properties of the heavy subunit of ratkidney gamma-glutamylcysteine synthetase. J Biol Chem,1993.268(26): p.19675-80.
    167. Dickinson, D.A. and H.J. Forman, Cellular glutathione and thiols metabolism.Biochem Pharmacol,2002.64(5-6): p.1019-26.
    168. Dalton, T.P., et al., Genetically altered mice to evaluate glutathione homeostasisin health and disease. Free Radic Biol Med,2004.37(10): p.1511-26.
    169. Farooqui, M.Y., W.W. Day, and D.M. Zamorano, Glutathione and lipidperoxidation in the aging rat. Comp Biochem Physiol B,1987.88(1): p.177-80.
    170. Rebrin, I., S. Kamzalov, and R.S. Sohal, Effects of age and caloric restriction onglutathione redox state in mice. Free Radic Biol Med,2003.35(6): p.626-35.
    171. Richie, J.P., Jr., C.A. Lang, and T.S. Chen, Acetaminophen-induced depletion ofglutathione and cysteine in the aging mouse kidney. Biochem Pharmacol,1992.44(1): p.129-35.
    172. Teramoto, S., et al., Age-related changes in the antioxidant screen of the distallung in mice. Lung,1994.172(4): p.223-30.
    173. Wu, T., et al., Ataxia: an early indicator in high altitude cerebral edema. High AltMed Biol,2006.7(4): p.275-80.
    174. Sandhu, S.K. and G. Kaur, Alterations in oxidative stress scavenger system inaging rat brain and lymphocytes. Biogerontology,2002.3(3): p.161-73.
    175. Liu, R. and J. Choi, Age-associated decline in gamma-glutamylcysteine synthetasegene expression in rats. Free Radic Biol Med,2000.28(4): p.566-74.
    176. Wang, H., H. Liu, and R.M. Liu, Gender difference in glutathione metabolismduring aging in mice. Exp Gerontol,2003.38(5): p.507-17.
    177. Kovacs, E.J., et al., Aging and innate immunity in the mouse: impact of intrinsicand extrinsic factors. Trends Immunol,2009.30(7): p.319-24.
    178. Cohn, J.R., C.A. Hohl, and C.E. Buckley, The Relationship between CutaneousCellular Immune Responsiveness and Mortality in a Nursing-Home Population. Journal of theAmerican Geriatrics Society,1983.31(12): p.808-809.
    179. Meakins, J.L., et al., Delayed hypersensitivity: indicator of acquired failure ofhost defenses in sepsis and trauma. Ann Surg,1977.186(3): p.241-50.
    180. Wayne, S.J., et al., Cell-mediated immunity as a predictor of morbidity andmortality in subjects over60. J Gerontol,1990.45(2): p. M45-8.
    181. Kumar, R. and E.A. Burns, Age-related decline in immunity: implications forvaccine responsiveness. Expert Rev Vaccines,2008.7(4): p.467-79.
    182. Gomez, C.R., et al., Innate immunity and aging. Exp Gerontol,2008.43(8): p.718-28.
    183. McGlauchlen, K.S. and L.A. Vogel, Ineffective humoral immunity in the elderly.Microbes Infect,2003.5(13): p.1279-84.
    184. Schriner, S.E., et al., Protection of human cultured cells against oxidative stressby Rhodiola rosea without activation of antioxidant defenses. Free Radical Biology andMedicine,2009.47(5): p.577-584.
    185. Bogden, J.D. and D.B. Louria, Aging and the immune system: the role ofmicronutrient nutrition. Nutrition,1999.15(7-8): p.593-5.
    186. Kemp FW, D.J., Li WJ, Bruening K, Baker H, Rigassio D, Bendich A, Bogden JD,Relationships between immunity and dietary and serum antioxidants, trace metals, B vitamins,and homocysteine in elderly men and women. Nutr Res,2002.22((1-2)): p.45-53.
    187. Meydani, S.N., et al., Vitamin E supplementation and in vivo immune response inhealthy elderly subjects. A randomized controlled trial. JAMA,1997.277(17): p.1380-6.
    188. Vidal, K., et al., Intake of a milk-based wolfberry formulation enhances theimmune response of young-adult and aged mice. Rejuvenation Res,2010.13(1): p.47-53.
    189. Winklhofer-Roob, B.M., et al., Effects of vitamin E and carotenoid status onoxidative stress in health and disease. Evidence obtained from human intervention studies.Mol Aspects Med,2003.24(6): p.391-402.
    190. Zhu, Y., et al., Salidroside protects against hydrogen peroxide-induced injury incardiac H9c2cells via PI3K-Akt dependent pathway. DNA Cell Biol,2011.30(10): p.809-19.
    191. Szendi, I., et al., Two subgroups of schizophrenia identified by systematiccognitive neuropsychiatric mapping. Eur Arch Psychiatry Clin Neurosci,2010.260(3): p.257-66.
    192. Haynes, L. and A.C. Maue, Effects of aging on T cell function. Curr OpinImmunol,2009.21(4): p.414-7.
    193. Bogden, J.D., et al., Daily micronutrient supplements enhancedelayed-hypersensitivity skin test responses in older people. Am J Clin Nutr,1994.60(3): p.437-47.
    194. Pallast, E.G., et al., Effect of50-and100-mg vitamin E supplements on cellularimmune function in noninstitutionalized elderly persons. Am J Clin Nutr,1999.69(6): p.1273-81.
    195. Vos, A.P., et al., A specific prebiotic oligosaccharide mixture stimulatesdelayed-type hypersensitivity in a murine influenza vaccination model. Int Immunopharmacol,
    2006.6(8): p.1277-86.
    196. Wu, D., et al., Dietary supplementation with mushroom-derived protein-boundglucan does not enhance immune function in young and old mice. J Nutr,1998.128(2): p.193-7.
    197. Linton, P.J. and K. Dorshkind, Age-related changes in lymphocyte developmentand function. Nat Immunol,2004.5(2): p.133-9.
    198. Frasca, D., R.L. Riley, and B.B. Blomberg, Humoral immune response and B-cellfunctions including immunoglobulin class switch are downregulated in aged mice and humans.Semin Immunol,2005.17(5): p.378-84.
    199. Smith, T.P., S.L. Kennedy, and M. Fleshner, Influence of age and physical activityon the primary in vivo antibody and T cell-mediated responses in men. J Appl Physiol,2004.97(2): p.491-8.
    200. Cortes-Wanstreet, M.M., et al., Overexpression of glutamate-cysteine ligaseprotects human COV434granulosa tumour cells against oxidative andgamma-radiation-induced cell death. Mutagenesis,2009.24(3): p.211-24.
    201. Hall, A.G., Review: The role of glutathione in the regulation of apoptosis. Eur JClin Invest,1999.29(3): p.238-45.
    202. Manna, S.K., M.T. Kuo, and B.B. Aggarwal, Overexpression ofgamma-glutamylcysteine synthetase suppresses tumor necrosis factor-induced apoptosis andactivation of nuclear transcription factor-kappa B and activator protein-1. Oncogene,1999.18(30): p.4371-82.
    203. Ziegler, D.M., Role of reversible oxidation-reduction of enzyme thiols-disulfidesin metabolic regulation. Annu Rev Biochem,1985.54: p.305-29.
    204. McConnachie, L.A., et al., Glutamate cysteine ligase modifier subunit deficiencyand gender as determinants of acetaminophen-induced hepatotoxicity in mice. Toxicol Sci,
    2007.99(2): p.628-36.
    205. Dalton, T.P., et al., Knockout of the mouse glutamate cysteine ligase catalyticsubunit (Gclc) gene: embryonic lethal when homozygous, and proposed model for moderateglutathione deficiency when heterozygous. Biochem Biophys Res Commun,2000.279(2): p.324-9.
    206. Griffith, O.W. and R.T. Mulcahy, The enzymes of glutathione synthesis:gamma-glutamylcysteine synthetase. Adv Enzymol Relat Areas Mol Biol,1999.73: p.209-67,xii.
    207. Shi, M.M., et al., Quinone-induced oxidative stress elevates glutathione andinduces gamma-glutamylcysteine synthetase activity in rat lung epithelial L2cells. J BiolChem,1994.269(42): p.26512-7.
    208. Suh, J.H., et al., Decline in transcriptional activity of Nrf2causes age-related lossof glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci U S A,2004.101(10): p.3381-6.
    209. Orr, W.C., et al., Overexpression of glutamate-cysteine ligase extends life span inDrosophila melanogaster. J Biol Chem,2005.280(45): p.37331-8.
    210. Lu, L., J. Yuan, and S. Zhang, Rejuvenating activity of salidroside (SDS): dietaryintake of SDS enhances the immune response of aged rats. Age (Dordr),2012.
    211. Hazelton, G.A. and C.A. Lang, Glutathione contents of tissues in the aging mouse.Biochem J,1980.188(1): p.25-30.
    212. Guan, S., et al., Salidroside Attenuates Hydrogen Peroxide-Induced Cell DamageThrough a cAMP-Dependent Pathway. Molecules,2011.16(4): p.3371-3379.
    213. Bailey-Downs, L.C., et al., Liver-specific knockdown of IGF-1decreases vascularoxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novelmodel of vascular aging. The Journals of Gerontology Series A: Biological Sciences andMedical Sciences,2012.67(4): p.313-329.

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