Skip to main content
Top
Published in: Immunity & Ageing 1/2020

Open Access 01-12-2020 | Review

Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging

Authors: Rachel Thomas, Weikan Wang, Dong-Ming Su

Published in: Immunity & Ageing | Issue 1/2020

Login to get access

Abstract

Immune system aging is characterized by the paradox of immunosenescence (insufficiency) and inflammaging (over-reaction), which incorporate two sides of the same coin, resulting in immune disorder. Immunosenescence refers to disruption in the structural architecture of immune organs and dysfunction in immune responses, resulting from both aged innate and adaptive immunity. Inflammaging, described as a chronic, sterile, systemic inflammatory condition associated with advanced age, is mainly attributed to somatic cellular senescence-associated secretory phenotype (SASP) and age-related autoimmune predisposition. However, the inability to reduce senescent somatic cells (SSCs), because of immunosenescence, exacerbates inflammaging. Age-related adaptive immune system deviations, particularly altered T cell function, are derived from age-related thymic atrophy or involution, a hallmark of thymic aging. Recently, there have been major developments in understanding how age-related thymic involution contributes to inflammaging and immunosenescence at the cellular and molecular levels, including genetic and epigenetic regulation, as well as developments of many potential rejuvenation strategies. Herein, we discuss the research progress uncovering how age-related thymic involution contributes to immunosenescence and inflammaging, as well as their intersection. We also describe how T cell adaptive immunity mediates inflammaging and plays a crucial role in the progression of age-related neurological and cardiovascular diseases, as well as cancer. We then briefly outline the underlying cellular and molecular mechanisms of age-related thymic involution, and finally summarize potential rejuvenation strategies to restore aged thymic function.
Literature
1.
4.
go back to reference Pawelec G, Wagner W, Adibzadeh M, Engel A. T cell immunosenescence in vitro and in vivo. Exp Gerontol. 1999;34(3):419–29.PubMedCrossRef Pawelec G, Wagner W, Adibzadeh M, Engel A. T cell immunosenescence in vitro and in vivo. Exp Gerontol. 1999;34(3):419–29.PubMedCrossRef
5.
go back to reference Nikolich-Zugich J. The twilight of immunity: emerging concepts in aging of the immune system. Nat Immun. 2018;19(1):10–9.CrossRef Nikolich-Zugich J. The twilight of immunity: emerging concepts in aging of the immune system. Nat Immun. 2018;19(1):10–9.CrossRef
10.
go back to reference Rezzani R, Nardo L, Favero G, Peroni M, Rodella LF. Thymus and aging: morphological, radiological, and functional overview. Age (Dordr). 2014;36(1):313–51.CrossRef Rezzani R, Nardo L, Favero G, Peroni M, Rodella LF. Thymus and aging: morphological, radiological, and functional overview. Age (Dordr). 2014;36(1):313–51.CrossRef
12.
go back to reference Xia J, Wang H, Guo J, Zhang Z, Coder B, Su DM. Age-Related Disruption of Steady-State Thymic Medulla Provokes Autoimmune Phenotype via Perturbing Negative Selection. Aging Dis. 2012;3(3):248–59.PubMedPubMedCentral Xia J, Wang H, Guo J, Zhang Z, Coder B, Su DM. Age-Related Disruption of Steady-State Thymic Medulla Provokes Autoimmune Phenotype via Perturbing Negative Selection. Aging Dis. 2012;3(3):248–59.PubMedPubMedCentral
13.
go back to reference Coder BD, Wang H, Ruan L, Su DM. Thymic involution perturbs negative selection leading to autoreactive T cells that induce chronic inflammation. J Immunol (Baltimore, Md : 1950). 2015;194(12):5825–37.CrossRef Coder BD, Wang H, Ruan L, Su DM. Thymic involution perturbs negative selection leading to autoreactive T cells that induce chronic inflammation. J Immunol (Baltimore, Md : 1950). 2015;194(12):5825–37.CrossRef
15.
go back to reference De Martinis M, Franceschi C, Monti D, Ginaldi L. Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett. 2005;579(10):2035–9.PubMedCrossRef De Martinis M, Franceschi C, Monti D, Ginaldi L. Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett. 2005;579(10):2035–9.PubMedCrossRef
16.
go back to reference Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244–54.PubMedCrossRef Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244–54.PubMedCrossRef
17.
go back to reference Brunner S, Herndler-Brandstetter D, Weinberger B, Grubeck-Loebenstein B. Persistent viral infections and immune aging. Ageing Res Rev. 2011;10(3):362–9.PubMedCrossRef Brunner S, Herndler-Brandstetter D, Weinberger B, Grubeck-Loebenstein B. Persistent viral infections and immune aging. Ageing Res Rev. 2011;10(3):362–9.PubMedCrossRef
18.
go back to reference Freund A, Orjalo AV, Desprez PY, Campisi J. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med. 2010;16(5):238–46.PubMedPubMedCentralCrossRef Freund A, Orjalo AV, Desprez PY, Campisi J. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med. 2010;16(5):238–46.PubMedPubMedCentralCrossRef
19.
go back to reference Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev. 2007;128(1):92–105.PubMedCrossRef Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev. 2007;128(1):92–105.PubMedCrossRef
20.
go back to reference Callender LA, Carroll EC, Beal RWJ, Chambers ES, Nourshargh S, Akbar AN, et al. Human CD8(+) EMRA T cells display a senescence-associated secretory phenotype regulated by p38 MAPK. Aging Cell. 2018;17:1.CrossRef Callender LA, Carroll EC, Beal RWJ, Chambers ES, Nourshargh S, Akbar AN, et al. Human CD8(+) EMRA T cells display a senescence-associated secretory phenotype regulated by p38 MAPK. Aging Cell. 2018;17:1.CrossRef
21.
go back to reference Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008;6(12):2853–68.PubMedCrossRef Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008;6(12):2853–68.PubMedCrossRef
22.
go back to reference Coppe JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99–118.PubMedPubMedCentralCrossRef Coppe JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99–118.PubMedPubMedCentralCrossRef
23.
go back to reference Fulop T, Witkowski JM, Olivieri F, Larbi A. The integration of inflammaging in age-related diseases. Semin Immunol. 2018;40:17–35.PubMedCrossRef Fulop T, Witkowski JM, Olivieri F, Larbi A. The integration of inflammaging in age-related diseases. Semin Immunol. 2018;40:17–35.PubMedCrossRef
24.
go back to reference Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA, et al. Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes? Front Immunol. 2017;8:1960.PubMedCrossRef Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA, et al. Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes? Front Immunol. 2017;8:1960.PubMedCrossRef
25.
go back to reference Gui J, Mustachio LM, Su DM, Craig RW. Thymus Size and Age-related Thymic Involution: Early Programming, Sexual Dimorphism, Progenitors and Stroma. Aging Dis. 2012;3(3):280–90.PubMedPubMedCentral Gui J, Mustachio LM, Su DM, Craig RW. Thymus Size and Age-related Thymic Involution: Early Programming, Sexual Dimorphism, Progenitors and Stroma. Aging Dis. 2012;3(3):280–90.PubMedPubMedCentral
26.
go back to reference Palmer S, Albergante L, Blackburn CC, Newman TJ. Thymic involution and rising disease incidence with age. Proc Natl Acad Sci U S A. 2018;115(8):1883–8.PubMedPubMedCentralCrossRef Palmer S, Albergante L, Blackburn CC, Newman TJ. Thymic involution and rising disease incidence with age. Proc Natl Acad Sci U S A. 2018;115(8):1883–8.PubMedPubMedCentralCrossRef
27.
go back to reference Fulop T, Dupuis G, Witkowski JM, Larbi A. The Role of Immunosenescence in the Development of Age-Related Diseases. Rev Investig Clin. 2016;68(2):84–91. Fulop T, Dupuis G, Witkowski JM, Larbi A. The Role of Immunosenescence in the Development of Age-Related Diseases. Rev Investig Clin. 2016;68(2):84–91.
28.
go back to reference Dai X, Zhang D, Wang C, Wu Z, Liang C. The Pivotal Role of Thymus in Atherosclerosis Mediated by Immune and Inflammatory Response. Int J Med Sci. 2018;15(13):1555–63.PubMedPubMedCentralCrossRef Dai X, Zhang D, Wang C, Wu Z, Liang C. The Pivotal Role of Thymus in Atherosclerosis Mediated by Immune and Inflammatory Response. Int J Med Sci. 2018;15(13):1555–63.PubMedPubMedCentralCrossRef
30.
go back to reference Palmer E. Negative selection--clearing out the bad apples from the T-cell repertoire. Nat Rev Immunol. 2003;3(5):383–91.PubMedCrossRef Palmer E. Negative selection--clearing out the bad apples from the T-cell repertoire. Nat Rev Immunol. 2003;3(5):383–91.PubMedCrossRef
31.
go back to reference Hsieh CS, Lee HM, Lio CW. Selection of regulatory T cells in the thymus. Nat Rev Immunol. 2012;12(3):157–67.PubMedCrossRef Hsieh CS, Lee HM, Lio CW. Selection of regulatory T cells in the thymus. Nat Rev Immunol. 2012;12(3):157–67.PubMedCrossRef
32.
go back to reference Cebula A, Seweryn M, Rempala GA, Pabla SS, McIndoe RA, Denning TL, et al. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature. 2013;497(7448):258–62.PubMedPubMedCentralCrossRef Cebula A, Seweryn M, Rempala GA, Pabla SS, McIndoe RA, Denning TL, et al. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature. 2013;497(7448):258–62.PubMedPubMedCentralCrossRef
33.
35.
go back to reference Min H, Montecino-Rodriguez E, Dorshkind K. Reduction in the developmental potential of intrathymic T cell progenitors with age. J Immunol (Baltimore, Md : 1950). 2004;173(1):245–50.CrossRef Min H, Montecino-Rodriguez E, Dorshkind K. Reduction in the developmental potential of intrathymic T cell progenitors with age. J Immunol (Baltimore, Md : 1950). 2004;173(1):245–50.CrossRef
36.
go back to reference Kovtonyuk LV, Fritsch K, Feng X, Manz MG, Takizawa H. Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment. Front Immunol. 2016;7:502.PubMedPubMedCentralCrossRef Kovtonyuk LV, Fritsch K, Feng X, Manz MG, Takizawa H. Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment. Front Immunol. 2016;7:502.PubMedPubMedCentralCrossRef
37.
go back to reference Latchney SE, Calvi LM. The aging hematopoietic stem cell niche: Phenotypic and functional changes and mechanisms that contribute to hematopoietic aging. Semin Hematol. 2017;54(1):25–32.PubMedCrossRef Latchney SE, Calvi LM. The aging hematopoietic stem cell niche: Phenotypic and functional changes and mechanisms that contribute to hematopoietic aging. Semin Hematol. 2017;54(1):25–32.PubMedCrossRef
38.
go back to reference Sun L, Brown R, Chen S, Zhuge Q, Su DM. Aging induced decline in T-lymphopoiesis is primarily dependent on status of progenitor niches in the bone marrow and thymus. Aging. 2012;4(9):606–19.PubMedPubMedCentralCrossRef Sun L, Brown R, Chen S, Zhuge Q, Su DM. Aging induced decline in T-lymphopoiesis is primarily dependent on status of progenitor niches in the bone marrow and thymus. Aging. 2012;4(9):606–19.PubMedPubMedCentralCrossRef
39.
go back to reference Su DM, Aw D, Palmer DB. Immunosenescence: a product of the environment? Curr Opin Immunol. 2013;25(4):498–503.PubMedCrossRef Su DM, Aw D, Palmer DB. Immunosenescence: a product of the environment? Curr Opin Immunol. 2013;25(4):498–503.PubMedCrossRef
40.
go back to reference Anderson G, Jenkinson EJ. Lymphostromal interactions in thymic development and function. Nat Rev Immunol. 2001;1(1):31–40.PubMedCrossRef Anderson G, Jenkinson EJ. Lymphostromal interactions in thymic development and function. Nat Rev Immunol. 2001;1(1):31–40.PubMedCrossRef
41.
go back to reference Klein L, Kyewski B, Allen PM, Hogquist KA. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat Rev Immunol. 2014;14(6):377–91.PubMedPubMedCentralCrossRef Klein L, Kyewski B, Allen PM, Hogquist KA. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat Rev Immunol. 2014;14(6):377–91.PubMedPubMedCentralCrossRef
44.
46.
go back to reference Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621.PubMedCrossRef Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621.PubMedCrossRef
48.
go back to reference Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of Cellular Senescence. Trends Cell Biol. 2018;28(6):436–53.PubMedCrossRef Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of Cellular Senescence. Trends Cell Biol. 2018;28(6):436–53.PubMedCrossRef
49.
go back to reference Campisi J. Cellular senescence: putting the paradoxes in perspective. Curr Opin Genet Dev. 2011;21(1):107–12.PubMedCrossRef Campisi J. Cellular senescence: putting the paradoxes in perspective. Curr Opin Genet Dev. 2011;21(1):107–12.PubMedCrossRef
50.
go back to reference Marcotte R, Lacelle C, Wang E. Senescent fibroblasts resist apoptosis by downregulating caspase-3. Mech Ageing Dev. 2004;125(10-11):777–83.PubMedCrossRef Marcotte R, Lacelle C, Wang E. Senescent fibroblasts resist apoptosis by downregulating caspase-3. Mech Ageing Dev. 2004;125(10-11):777–83.PubMedCrossRef
51.
go back to reference Sanders YY, Liu H, Zhang X, Hecker L, Bernard K, Desai L, et al. Histone modifications in senescence-associated resistance to apoptosis by oxidative stress. Redox Biol. 2013;1:8–16.PubMedPubMedCentralCrossRef Sanders YY, Liu H, Zhang X, Hecker L, Bernard K, Desai L, et al. Histone modifications in senescence-associated resistance to apoptosis by oxidative stress. Redox Biol. 2013;1:8–16.PubMedPubMedCentralCrossRef
53.
go back to reference Fukushima Y, Minato N, Hattori M. The impact of senescence-associated T cells on immunosenescence and age-related disorders. Inflamm Regen. 2018;38:24.PubMedPubMedCentralCrossRef Fukushima Y, Minato N, Hattori M. The impact of senescence-associated T cells on immunosenescence and age-related disorders. Inflamm Regen. 2018;38:24.PubMedPubMedCentralCrossRef
54.
go back to reference Crespo J, Sun H, Welling TH, Tian Z, Zou W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol. 2013;25(2):214–21.PubMedPubMedCentralCrossRef Crespo J, Sun H, Welling TH, Tian Z, Zou W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol. 2013;25(2):214–21.PubMedPubMedCentralCrossRef
55.
go back to reference Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New Engl J Med. 2012;366(26):2443–54.PubMedCrossRef Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New Engl J Med. 2012;366(26):2443–54.PubMedCrossRef
56.
go back to reference Prata L, Ovsyannikova IG, Tchkonia T, Kirkland JL. Senescent cell clearance by the immune system: Emerging therapeutic opportunities. Semin Immunol. 2018;40:101275.PubMedCrossRef Prata L, Ovsyannikova IG, Tchkonia T, Kirkland JL. Senescent cell clearance by the immune system: Emerging therapeutic opportunities. Semin Immunol. 2018;40:101275.PubMedCrossRef
57.
go back to reference Burton DGA, Stolzing A. Cellular senescence: Immunosurveillance and future immunotherapy. Ageing Res Rev. 2018;43:17–25.PubMedCrossRef Burton DGA, Stolzing A. Cellular senescence: Immunosurveillance and future immunotherapy. Ageing Res Rev. 2018;43:17–25.PubMedCrossRef
58.
go back to reference Sagiv A, Biran A, Yon M, Simon J, Lowe SW, Krizhanovsky V. Granule exocytosis mediates immune surveillance of senescent cells. Oncogene. 2013;32(15):1971–7.PubMedCrossRef Sagiv A, Biran A, Yon M, Simon J, Lowe SW, Krizhanovsky V. Granule exocytosis mediates immune surveillance of senescent cells. Oncogene. 2013;32(15):1971–7.PubMedCrossRef
59.
go back to reference Plowden J, Renshaw-Hoelscher M, Engleman C, Katz J, Sambhara S. Innate immunity in aging: impact on macrophage function. Aging Cell. 2004;3(4):161–7.PubMedCrossRef Plowden J, Renshaw-Hoelscher M, Engleman C, Katz J, Sambhara S. Innate immunity in aging: impact on macrophage function. Aging Cell. 2004;3(4):161–7.PubMedCrossRef
60.
go back to reference Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T. Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol. 2012;24(5):331–41.PubMedCrossRef Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T. Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol. 2012;24(5):331–41.PubMedCrossRef
61.
go back to reference Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013;123(3):966–72.PubMedPubMedCentralCrossRef Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013;123(3):966–72.PubMedPubMedCentralCrossRef
62.
go back to reference Franceschi C, Zaikin A, Gordleeva S, Ivanchenko M, Bonifazi F, Storci G, et al. Inflammaging 2018: An update and a model. Semin Immunol. 2018;40:1–5.PubMedCrossRef Franceschi C, Zaikin A, Gordleeva S, Ivanchenko M, Bonifazi F, Storci G, et al. Inflammaging 2018: An update and a model. Semin Immunol. 2018;40:1–5.PubMedCrossRef
63.
go back to reference Nikolich-Zugich J. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol. 2008;8(7):512–22.PubMedPubMedCentralCrossRef Nikolich-Zugich J. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol. 2008;8(7):512–22.PubMedPubMedCentralCrossRef
64.
go back to reference High KP, Akbar AN, Nikolich-Zugich J. Translational research in immune senescence: Assessing the relevance of current models. Semin Immunol. 2012;24(5):373–82.PubMedPubMedCentralCrossRef High KP, Akbar AN, Nikolich-Zugich J. Translational research in immune senescence: Assessing the relevance of current models. Semin Immunol. 2012;24(5):373–82.PubMedPubMedCentralCrossRef
66.
go back to reference Olsson J, Wikby A, Johansson B, Lofgren S, Nilsson BO, Ferguson FG. Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study. Mech Ageing Dev. 2000;121(1-3):187–201.PubMedCrossRef Olsson J, Wikby A, Johansson B, Lofgren S, Nilsson BO, Ferguson FG. Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study. Mech Ageing Dev. 2000;121(1-3):187–201.PubMedCrossRef
67.
go back to reference Wikby A, Johansson B, Olsson J, Lofgren S, Nilsson BO, Ferguson F. Expansions of peripheral blood CD8 T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: the Swedish NONA immune study. Exp Gerontol. 2002;37(2-3):445–53.PubMedCrossRef Wikby A, Johansson B, Olsson J, Lofgren S, Nilsson BO, Ferguson F. Expansions of peripheral blood CD8 T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: the Swedish NONA immune study. Exp Gerontol. 2002;37(2-3):445–53.PubMedCrossRef
69.
go back to reference Petrie HT. Role of thymic organ structure and stromal composition in steady-state postnatal T-cell production. Immunol Rev. 2002;189:8–19.PubMedCrossRef Petrie HT. Role of thymic organ structure and stromal composition in steady-state postnatal T-cell production. Immunol Rev. 2002;189:8–19.PubMedCrossRef
72.
go back to reference Franceschi C, Valensin S, Fagnoni F, Barbi C, Bonafe M. Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load. Exp Gerontol. 1999;34(8):911–21.PubMedCrossRef Franceschi C, Valensin S, Fagnoni F, Barbi C, Bonafe M. Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load. Exp Gerontol. 1999;34(8):911–21.PubMedCrossRef
73.
go back to reference Tsukamoto H, Clise-Dwyer K, Huston GE, Duso DK, Buck AL, Johnson LL, et al. Age-associated increase in lifespan of naive CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects. Proc Natl Acad Sci U S A. 2009;106(43):18333–8.PubMedPubMedCentralCrossRef Tsukamoto H, Clise-Dwyer K, Huston GE, Duso DK, Buck AL, Johnson LL, et al. Age-associated increase in lifespan of naive CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects. Proc Natl Acad Sci U S A. 2009;106(43):18333–8.PubMedPubMedCentralCrossRef
74.
go back to reference Tsukamoto H, Huston GE, Dibble J, Duso DK, Swain SL. Bim dictates naive CD4 T cell lifespan and the development of age-associated functional defects. J Immunol (Baltimore, Md : 1950). 2010;185(8):4535–44.CrossRef Tsukamoto H, Huston GE, Dibble J, Duso DK, Swain SL. Bim dictates naive CD4 T cell lifespan and the development of age-associated functional defects. J Immunol (Baltimore, Md : 1950). 2010;185(8):4535–44.CrossRef
75.
go back to reference Chougnet CA, Tripathi P, Lages CS, Raynor J, Sholl A, Fink P, et al. A major role for Bim in regulatory T cell homeostasis. J Immunol (Baltimore, Md : 1950). 2011;186(1):156–63.CrossRef Chougnet CA, Tripathi P, Lages CS, Raynor J, Sholl A, Fink P, et al. A major role for Bim in regulatory T cell homeostasis. J Immunol (Baltimore, Md : 1950). 2011;186(1):156–63.CrossRef
76.
go back to reference Gui J, Zhu X, Dohkan J, Cheng L, Barnes PF, Su DM. The aged thymus shows normal recruitment of lymphohematopoietic progenitors but has defects in thymic epithelial cells. Int Immunol. 2007;19(10):1201–11.PubMedCrossRef Gui J, Zhu X, Dohkan J, Cheng L, Barnes PF, Su DM. The aged thymus shows normal recruitment of lymphohematopoietic progenitors but has defects in thymic epithelial cells. Int Immunol. 2007;19(10):1201–11.PubMedCrossRef
80.
go back to reference Ferreira C, Singh Y, Furmanski AL, Wong FS, Garden OA, Dyson J. Non-obese diabetic mice select a low-diversity repertoire of natural regulatory T cells. Proc Natl Acad Sci U S A. 2009;106(20):8320–5.PubMedPubMedCentralCrossRef Ferreira C, Singh Y, Furmanski AL, Wong FS, Garden OA, Dyson J. Non-obese diabetic mice select a low-diversity repertoire of natural regulatory T cells. Proc Natl Acad Sci U S A. 2009;106(20):8320–5.PubMedPubMedCentralCrossRef
81.
go back to reference Ferreira C, Palmer D, Blake K, Garden OA, Dyson J. Reduced regulatory T cell diversity in NOD mice is linked to early events in the thymus. J Immunol (Baltimore, Md : 1950). 2014;192(9):4145–52.CrossRef Ferreira C, Palmer D, Blake K, Garden OA, Dyson J. Reduced regulatory T cell diversity in NOD mice is linked to early events in the thymus. J Immunol (Baltimore, Md : 1950). 2014;192(9):4145–52.CrossRef
82.
go back to reference Stritesky GL, Jameson SC, Hogquist KA. Selection of self-reactive T cells in the thymus. Annu Rev Immunol. 2012;30:95–114.PubMedCrossRef Stritesky GL, Jameson SC, Hogquist KA. Selection of self-reactive T cells in the thymus. Annu Rev Immunol. 2012;30:95–114.PubMedCrossRef
84.
86.
go back to reference Fletcher AL, Seach N, Reiseger JJ, Lowen TE, Hammett MV, Scott HS, et al. Reduced thymic Aire expression and abnormal NF-kappaB2 signaling in a model of systemic autoimmunity. J Immunol. 2009;182(5):2690–9.PubMedCrossRef Fletcher AL, Seach N, Reiseger JJ, Lowen TE, Hammett MV, Scott HS, et al. Reduced thymic Aire expression and abnormal NF-kappaB2 signaling in a model of systemic autoimmunity. J Immunol. 2009;182(5):2690–9.PubMedCrossRef
87.
go back to reference Klein L, Robey EA, Hsieh CS. Central CD4(+) T cell tolerance: deletion versus regulatory T cell differentiation. Nat Rev Immunol. 2019;19(1):7–18.PubMedCrossRef Klein L, Robey EA, Hsieh CS. Central CD4(+) T cell tolerance: deletion versus regulatory T cell differentiation. Nat Rev Immunol. 2019;19(1):7–18.PubMedCrossRef
88.
go back to reference Pohar J, Simon Q, Fillatreau S. Antigen-Specificity in the Thymic Development and Peripheral Activity of CD4 (+) FOXP3 (+) T Regulatory Cells. Front Immunol. 2018;9:1701.PubMedPubMedCentralCrossRef Pohar J, Simon Q, Fillatreau S. Antigen-Specificity in the Thymic Development and Peripheral Activity of CD4 (+) FOXP3 (+) T Regulatory Cells. Front Immunol. 2018;9:1701.PubMedPubMedCentralCrossRef
89.
go back to reference Lathrop SK, Santacruz NA, Pham D, Luo J, Hsieh CS. Antigen-specific peripheral shaping of the natural regulatory T cell population. J Exp Med. 2008;205(13):3105–17.PubMedPubMedCentralCrossRef Lathrop SK, Santacruz NA, Pham D, Luo J, Hsieh CS. Antigen-specific peripheral shaping of the natural regulatory T cell population. J Exp Med. 2008;205(13):3105–17.PubMedPubMedCentralCrossRef
90.
go back to reference Wirnsberger G, Hinterberger M, Klein L. Regulatory T-cell differentiation versus clonal deletion of autoreactive thymocytes. Immunol Cell Biol. 2011;89(1):45–53.PubMedCrossRef Wirnsberger G, Hinterberger M, Klein L. Regulatory T-cell differentiation versus clonal deletion of autoreactive thymocytes. Immunol Cell Biol. 2011;89(1):45–53.PubMedCrossRef
91.
go back to reference Hinterberger M, Aichinger M. Prazeres da Costa O, Voehringer D, Hoffmann R, Klein L. Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat Immun. 2010;11(6):512–9.CrossRef Hinterberger M, Aichinger M. Prazeres da Costa O, Voehringer D, Hoffmann R, Klein L. Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat Immun. 2010;11(6):512–9.CrossRef
92.
go back to reference Raynor J, Lages CS, Shehata H, Hildeman DA, Chougnet CA. Homeostasis and function of regulatory T cells in aging. Curr Opin Immunol. 2012;24(4):482–7.PubMedPubMedCentralCrossRef Raynor J, Lages CS, Shehata H, Hildeman DA, Chougnet CA. Homeostasis and function of regulatory T cells in aging. Curr Opin Immunol. 2012;24(4):482–7.PubMedPubMedCentralCrossRef
93.
go back to reference Jagger A, Shimojima Y, Goronzy JJ, Weyand CM. Regulatory T cells and the immune aging process: a mini-review. Gerontology. 2014;60(2):130–7.PubMedCrossRef Jagger A, Shimojima Y, Goronzy JJ, Weyand CM. Regulatory T cells and the immune aging process: a mini-review. Gerontology. 2014;60(2):130–7.PubMedCrossRef
94.
go back to reference Nishioka T, Shimizu J, Iida R, Yamazaki S, Sakaguchi S. CD4+CD25+Foxp3+ T cells and CD4+CD25-Foxp3+ T cells in aged mice. J Immunol (Baltimore, Md : 1950). 2006;176(11):6586–93.CrossRef Nishioka T, Shimizu J, Iida R, Yamazaki S, Sakaguchi S. CD4+CD25+Foxp3+ T cells and CD4+CD25-Foxp3+ T cells in aged mice. J Immunol (Baltimore, Md : 1950). 2006;176(11):6586–93.CrossRef
95.
go back to reference Darrigues J, van Meerwijk JPM, Romagnoli P. Age-Dependent Changes in Regulatory T Lymphocyte Development and Function: A Mini-Review. Gerontology. 2018;64(1):28–35.PubMedCrossRef Darrigues J, van Meerwijk JPM, Romagnoli P. Age-Dependent Changes in Regulatory T Lymphocyte Development and Function: A Mini-Review. Gerontology. 2018;64(1):28–35.PubMedCrossRef
96.
go back to reference Garg SK, Delaney C, Toubai T, Ghosh A, Reddy P, Banerjee R, et al. Aging is associated with increased regulatory T-cell function. Aging Cell. 2014;13(3):441–8.PubMedPubMedCentralCrossRef Garg SK, Delaney C, Toubai T, Ghosh A, Reddy P, Banerjee R, et al. Aging is associated with increased regulatory T-cell function. Aging Cell. 2014;13(3):441–8.PubMedPubMedCentralCrossRef
97.
go back to reference Malchow S, Leventhal DS, Lee V, Nishi S, Socci ND, Savage PA. Aire Enforces Immune Tolerance by Directing Autoreactive T Cells into the Regulatory T Cell Lineage. Immunity. 2016;44(5):1102–13.PubMedPubMedCentralCrossRef Malchow S, Leventhal DS, Lee V, Nishi S, Socci ND, Savage PA. Aire Enforces Immune Tolerance by Directing Autoreactive T Cells into the Regulatory T Cell Lineage. Immunity. 2016;44(5):1102–13.PubMedPubMedCentralCrossRef
98.
go back to reference Malchow S, Leventhal DS, Savage PA. Organ-specific regulatory T cells of thymic origin are expanded in murine prostate tumors. Oncoimmunology. 2013;2(7):e24898.PubMedPubMedCentralCrossRef Malchow S, Leventhal DS, Savage PA. Organ-specific regulatory T cells of thymic origin are expanded in murine prostate tumors. Oncoimmunology. 2013;2(7):e24898.PubMedPubMedCentralCrossRef
99.
go back to reference Kieback E, Hilgenberg E, Stervbo U, Lampropoulou V, Shen P, Bunse M, et al. Thymus-Derived Regulatory T Cells Are Positively Selected on Natural Self-Antigen through Cognate Interactions of High Functional Avidity. Immunity. 2016;44(5):1114–26.PubMedCrossRef Kieback E, Hilgenberg E, Stervbo U, Lampropoulou V, Shen P, Bunse M, et al. Thymus-Derived Regulatory T Cells Are Positively Selected on Natural Self-Antigen through Cognate Interactions of High Functional Avidity. Immunity. 2016;44(5):1114–26.PubMedCrossRef
100.
go back to reference Lages CS, Suffia I, Velilla PA, Huang B, Warshaw G, Hildeman DA, et al. Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation. J Immunol (Baltimore, Md : 1950). 2008;181(3):1835–48.CrossRef Lages CS, Suffia I, Velilla PA, Huang B, Warshaw G, Hildeman DA, et al. Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation. J Immunol (Baltimore, Md : 1950). 2008;181(3):1835–48.CrossRef
101.
go back to reference Coder B, Wang W, Wang L, Wu Z, Zhuge Q, Su DM. Friend or foe: the dichotomous impact of T cells on neuro-de/re-generation during aging. Oncotarget. 2016;8(4):7116–37. Coder B, Wang W, Wang L, Wu Z, Zhuge Q, Su DM. Friend or foe: the dichotomous impact of T cells on neuro-de/re-generation during aging. Oncotarget. 2016;8(4):7116–37.
102.
go back to reference Paneni F, Diaz Canestro C, Libby P, Luscher TF, Camici GG. The Aging Cardiovascular System: Understanding It at the Cellular and Clinical Levels. J Am Coll Cardiol. 2017;69(15):1952–67.PubMedCrossRef Paneni F, Diaz Canestro C, Libby P, Luscher TF, Camici GG. The Aging Cardiovascular System: Understanding It at the Cellular and Clinical Levels. J Am Coll Cardiol. 2017;69(15):1952–67.PubMedCrossRef
103.
104.
go back to reference Wong BW, Meredith A, Lin D, McManus BM. The biological role of inflammation in atherosclerosis. Can J Cardiol. 2012;28(6):631–41.PubMedCrossRef Wong BW, Meredith A, Lin D, McManus BM. The biological role of inflammation in atherosclerosis. Can J Cardiol. 2012;28(6):631–41.PubMedCrossRef
105.
go back to reference Costantini E, D'Angelo C, Reale M. The Role of Immunosenescence in Neurodegenerative Diseases. Mediat Inflamm. 2018;2018:6039171. Costantini E, D'Angelo C, Reale M. The Role of Immunosenescence in Neurodegenerative Diseases. Mediat Inflamm. 2018;2018:6039171.
106.
110.
go back to reference Chupel MU, Minuzzi LG, Furtado G, Santos ML, Hogervorst E, Filaire E, et al. Exercise and taurine in inflammation, cognition, and peripheral markers of blood-brain barrier integrity in older women. Appl Physiol Nutr Metab. 2018;43(7):733–41.PubMedCrossRef Chupel MU, Minuzzi LG, Furtado G, Santos ML, Hogervorst E, Filaire E, et al. Exercise and taurine in inflammation, cognition, and peripheral markers of blood-brain barrier integrity in older women. Appl Physiol Nutr Metab. 2018;43(7):733–41.PubMedCrossRef
111.
go back to reference Erickson MA, Banks WA. Neuroimmune Axes of the Blood-Brain Barriers and Blood-Brain Interfaces: Bases for Physiological Regulation, Disease States, and Pharmacological Interventions. Pharmacol Rev. 2018;70(2):278–314.PubMedPubMedCentralCrossRef Erickson MA, Banks WA. Neuroimmune Axes of the Blood-Brain Barriers and Blood-Brain Interfaces: Bases for Physiological Regulation, Disease States, and Pharmacological Interventions. Pharmacol Rev. 2018;70(2):278–314.PubMedPubMedCentralCrossRef
112.
go back to reference Liang Z, Zhao Y, Ruan L, Zhu L, Jin K, Zhuge Q, et al. Impact of aging immune system on neurodegeneration and potential immunotherapies. Prog Neurobiol. 2017;157:2–28.PubMedCrossRef Liang Z, Zhao Y, Ruan L, Zhu L, Jin K, Zhuge Q, et al. Impact of aging immune system on neurodegeneration and potential immunotherapies. Prog Neurobiol. 2017;157:2–28.PubMedCrossRef
113.
go back to reference Das R, Chinnathambi S. Microglial priming of antigen presentation and adaptive stimulation in Alzheimer’s disease. Cell Mol Life Sci. 2019;76(19):3681–94.PubMedCrossRef Das R, Chinnathambi S. Microglial priming of antigen presentation and adaptive stimulation in Alzheimer’s disease. Cell Mol Life Sci. 2019;76(19):3681–94.PubMedCrossRef
114.
go back to reference Browne TC, McQuillan K, McManus RM, O’Reilly JA, Mills KH, Lynch MA. IFN-gamma Production by amyloid beta-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease. J Immunol. 2013;190(5):2241–51.PubMedCrossRef Browne TC, McQuillan K, McManus RM, O’Reilly JA, Mills KH, Lynch MA. IFN-gamma Production by amyloid beta-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease. J Immunol. 2013;190(5):2241–51.PubMedCrossRef
115.
go back to reference Zhang J, Ke KF, Liu Z, Qiu YH, Peng YP. Th17 cell-mediated neuroinflammation is involved in neurodegeneration of abeta1-42-induced Alzheimer's disease model rats. PLoS One. 2013;8(10):e75786.PubMedPubMedCentralCrossRef Zhang J, Ke KF, Liu Z, Qiu YH, Peng YP. Th17 cell-mediated neuroinflammation is involved in neurodegeneration of abeta1-42-induced Alzheimer's disease model rats. PLoS One. 2013;8(10):e75786.PubMedPubMedCentralCrossRef
116.
go back to reference Yang H, Yang H, Xie Z, Wei L, Bi J. Systemic transplantation of human umbilical cord derived mesenchymal stem cells-educated T regulatory cells improved the impaired cognition in AbetaPPswe/PS1dE9 transgenic mice. PLoS One. 2013;8(7):e69129.PubMedPubMedCentralCrossRef Yang H, Yang H, Xie Z, Wei L, Bi J. Systemic transplantation of human umbilical cord derived mesenchymal stem cells-educated T regulatory cells improved the impaired cognition in AbetaPPswe/PS1dE9 transgenic mice. PLoS One. 2013;8(7):e69129.PubMedPubMedCentralCrossRef
117.
go back to reference Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A, et al. Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology. Nat Commun. 2015;6:7967.PubMedCrossRef Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A, et al. Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology. Nat Commun. 2015;6:7967.PubMedCrossRef
118.
go back to reference Cao C, Arendash GW, Dickson A, Mamcarz MB, Lin X, Ethell DW. Abeta-specific Th2 cells provide cognitive and pathological benefits to Alzheimer's mice without infiltrating the CNS. Neurobiol Dis. 2009;34(1):63–70.PubMedPubMedCentralCrossRef Cao C, Arendash GW, Dickson A, Mamcarz MB, Lin X, Ethell DW. Abeta-specific Th2 cells provide cognitive and pathological benefits to Alzheimer's mice without infiltrating the CNS. Neurobiol Dis. 2009;34(1):63–70.PubMedPubMedCentralCrossRef
119.
go back to reference Baruch K, Ron-Harel N, Gal H, Deczkowska A, Shifrut E, Ndifon W, et al. CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. Proc Natl Acad Sci U S A. 2013;110(6):2264–9.PubMedPubMedCentralCrossRef Baruch K, Ron-Harel N, Gal H, Deczkowska A, Shifrut E, Ndifon W, et al. CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. Proc Natl Acad Sci U S A. 2013;110(6):2264–9.PubMedPubMedCentralCrossRef
120.
go back to reference Ghersi-Egea JF, Strazielle N, Catala M, Silva-Vargas V, Doetsch F, Engelhardt B. Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease. Acta Neuropathol. 2018;135(3):337–61.PubMedCrossRef Ghersi-Egea JF, Strazielle N, Catala M, Silva-Vargas V, Doetsch F, Engelhardt B. Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease. Acta Neuropathol. 2018;135(3):337–61.PubMedCrossRef
121.
go back to reference Deczkowska A, Baruch K, Schwartz M. Type I/II Interferon Balance in the Regulation of Brain Physiology and Pathology. Trends Immunol. 2016;37(3):181–92.PubMedCrossRef Deczkowska A, Baruch K, Schwartz M. Type I/II Interferon Balance in the Regulation of Brain Physiology and Pathology. Trends Immunol. 2016;37(3):181–92.PubMedCrossRef
122.
go back to reference Kunis G, Baruch K, Rosenzweig N, Kertser A, Miller O, Berkutzki T, et al. IFN-gamma-dependent activation of the brain's choroid plexus for CNS immune surveillance and repair. Brain. 2013;136(Pt 11):3427–40.PubMedCrossRef Kunis G, Baruch K, Rosenzweig N, Kertser A, Miller O, Berkutzki T, et al. IFN-gamma-dependent activation of the brain's choroid plexus for CNS immune surveillance and repair. Brain. 2013;136(Pt 11):3427–40.PubMedCrossRef
123.
go back to reference Baruch K, Deczkowska A, David E, Castellano JM, Miller O, Kertser A, et al. Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science. 2014;346(6205):89–93.PubMedPubMedCentralCrossRef Baruch K, Deczkowska A, David E, Castellano JM, Miller O, Kertser A, et al. Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science. 2014;346(6205):89–93.PubMedPubMedCentralCrossRef
124.
go back to reference Sandmand M, Bruunsgaard H, Kemp K, Andersen-Ranberg K, Pedersen AN, Skinhoj P, et al. Is ageing associated with a shift in the balance between Type 1 and Type 2 cytokines in humans? Clin Exp Immunol. 2002;127(1):107–14.PubMedPubMedCentralCrossRef Sandmand M, Bruunsgaard H, Kemp K, Andersen-Ranberg K, Pedersen AN, Skinhoj P, et al. Is ageing associated with a shift in the balance between Type 1 and Type 2 cytokines in humans? Clin Exp Immunol. 2002;127(1):107–14.PubMedPubMedCentralCrossRef
125.
go back to reference Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87.PubMedCrossRef Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87.PubMedCrossRef
126.
go back to reference Xie L, Choudhury GR, Winters A, Yang SH, Jin K. Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10. Eur J Immunol. 2015;45(1):180–91.PubMedCrossRef Xie L, Choudhury GR, Winters A, Yang SH, Jin K. Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10. Eur J Immunol. 2015;45(1):180–91.PubMedCrossRef
127.
go back to reference Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation. 2011;123(8):933–44.PubMedCrossRef Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation. 2011;123(8):933–44.PubMedCrossRef
129.
go back to reference Del Pinto R, Ferri C. Inflammation-Accelerated Senescence and the Cardiovascular System: Mechanisms and Perspectives. Int J Mol Sci. 2018;19:12. Del Pinto R, Ferri C. Inflammation-Accelerated Senescence and the Cardiovascular System: Mechanisms and Perspectives. Int J Mol Sci. 2018;19:12.
130.
go back to reference Yu HT, Park S, Shin EC, Lee WW. T cell senescence and cardiovascular diseases. Clin Exp Med. 2016;16(3):257–63.PubMedCrossRef Yu HT, Park S, Shin EC, Lee WW. T cell senescence and cardiovascular diseases. Clin Exp Med. 2016;16(3):257–63.PubMedCrossRef
131.
go back to reference Stock J. Triglycerides and cardiovascular risk: Apolipoprotein B holds the key. Atherosclerosis. 2019;284:221–2.PubMedCrossRef Stock J. Triglycerides and cardiovascular risk: Apolipoprotein B holds the key. Atherosclerosis. 2019;284:221–2.PubMedCrossRef
132.
go back to reference Summerhill VI, Grechko AV, Yet SF, Sobenin IA, Orekhov AN. The Atherogenic Role of Circulating Modified Lipids in Atherosclerosis. Int J Mol Sci. 2019;20:14.CrossRef Summerhill VI, Grechko AV, Yet SF, Sobenin IA, Orekhov AN. The Atherogenic Role of Circulating Modified Lipids in Atherosclerosis. Int J Mol Sci. 2019;20:14.CrossRef
133.
go back to reference Shaw MK, Tse KY, Zhao X, Welch K, Eitzman DT, Thipparthi RR, et al. T-Cells Specific for a Self-Peptide of ApoB-100 Exacerbate Aortic Atheroma in Murine Atherosclerosis. Front Immunol. 2017;8:95.PubMedPubMedCentralCrossRef Shaw MK, Tse KY, Zhao X, Welch K, Eitzman DT, Thipparthi RR, et al. T-Cells Specific for a Self-Peptide of ApoB-100 Exacerbate Aortic Atheroma in Murine Atherosclerosis. Front Immunol. 2017;8:95.PubMedPubMedCentralCrossRef
134.
go back to reference Kimura T, Kobiyama K, Winkels H, Tse K, Miller J, Vassallo M, et al. Regulatory CD4(+) T Cells Recognize Major Histocompatibility Complex Class II Molecule-Restricted Peptide Epitopes of Apolipoprotein B. Circulation. 2018;138(11):1130–43.PubMedPubMedCentralCrossRef Kimura T, Kobiyama K, Winkels H, Tse K, Miller J, Vassallo M, et al. Regulatory CD4(+) T Cells Recognize Major Histocompatibility Complex Class II Molecule-Restricted Peptide Epitopes of Apolipoprotein B. Circulation. 2018;138(11):1130–43.PubMedPubMedCentralCrossRef
135.
go back to reference Fann M, Chiu WK, Wood WH 3rd, Levine BL, Becker KG, Weng NP. Gene expression characteristics of CD28null memory phenotype CD8+ T cells and its implication in T-cell aging. Immunol Rev. 2005;205:190–206.PubMedCrossRef Fann M, Chiu WK, Wood WH 3rd, Levine BL, Becker KG, Weng NP. Gene expression characteristics of CD28null memory phenotype CD8+ T cells and its implication in T-cell aging. Immunol Rev. 2005;205:190–206.PubMedCrossRef
136.
go back to reference Suarez-Alvarez B, Rodriguez RM, Schlangen K, Raneros AB, Marquez-Kisinousky L, Fernandez AF, et al. Phenotypic characteristics of aged CD4(+) CD28(null) T lymphocytes are determined by changes in the whole-genome DNA methylation pattern. Aging Cell. 2017;16(2):293–303.PubMedCrossRef Suarez-Alvarez B, Rodriguez RM, Schlangen K, Raneros AB, Marquez-Kisinousky L, Fernandez AF, et al. Phenotypic characteristics of aged CD4(+) CD28(null) T lymphocytes are determined by changes in the whole-genome DNA methylation pattern. Aging Cell. 2017;16(2):293–303.PubMedCrossRef
137.
go back to reference Leon ML, Zuckerman SH. Gamma interferon: a central mediator in atherosclerosis. Inflamm Res. 2005;54(10):395–411.PubMedCrossRef Leon ML, Zuckerman SH. Gamma interferon: a central mediator in atherosclerosis. Inflamm Res. 2005;54(10):395–411.PubMedCrossRef
138.
go back to reference Liuzzo G, Biasucci LM, Trotta G, Brugaletta S, Pinnelli M, Digianuario G, et al. Unusual CD4+CD28null T lymphocytes and recurrence of acute coronary events. J Am Coll Cardiol. 2007;50(15):1450–8.PubMedCrossRef Liuzzo G, Biasucci LM, Trotta G, Brugaletta S, Pinnelli M, Digianuario G, et al. Unusual CD4+CD28null T lymphocytes and recurrence of acute coronary events. J Am Coll Cardiol. 2007;50(15):1450–8.PubMedCrossRef
139.
go back to reference Ammirati E, Cianflone D, Vecchio V, Banfi M, Vermi AC, De Metrio M, et al. Effector Memory T cells Are Associated With Atherosclerosis in Humans and Animal Models. J Am Heart Assoc. 2012;1(1):27–41.PubMedPubMedCentralCrossRef Ammirati E, Cianflone D, Vecchio V, Banfi M, Vermi AC, De Metrio M, et al. Effector Memory T cells Are Associated With Atherosclerosis in Humans and Animal Models. J Am Heart Assoc. 2012;1(1):27–41.PubMedPubMedCentralCrossRef
141.
go back to reference Falci C, Gianesin K, Sergi G, Giunco S, De Ronch I, Valpione S, et al. Immune senescence and cancer in elderly patients: results from an exploratory study. Exp Gerontol. 2013;48(12):1436–42.PubMedCrossRef Falci C, Gianesin K, Sergi G, Giunco S, De Ronch I, Valpione S, et al. Immune senescence and cancer in elderly patients: results from an exploratory study. Exp Gerontol. 2013;48(12):1436–42.PubMedCrossRef
142.
go back to reference Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014:149185.PubMedPubMedCentralCrossRef Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014:149185.PubMedPubMedCentralCrossRef
143.
go back to reference Qi Q, Zhang DW, Weyand CM, Goronzy JJ. Mechanisms shaping the naive T cell repertoire in the elderly - thymic involution or peripheral homeostatic proliferation? Exp Gerontol. 2014;54:71–4.PubMedPubMedCentralCrossRef Qi Q, Zhang DW, Weyand CM, Goronzy JJ. Mechanisms shaping the naive T cell repertoire in the elderly - thymic involution or peripheral homeostatic proliferation? Exp Gerontol. 2014;54:71–4.PubMedPubMedCentralCrossRef
145.
go back to reference Chen HC, Eling N, Martinez-Jimenez CP, O'Brien LM, Carbonaro V, Marioni JC, et al. IL-7-dependent compositional changes within the gammadelta T cell pool in lymph nodes during ageing lead to an unbalanced anti-tumour response. EMBO Rep. 2019;20(8):e47379.PubMedPubMedCentralCrossRef Chen HC, Eling N, Martinez-Jimenez CP, O'Brien LM, Carbonaro V, Marioni JC, et al. IL-7-dependent compositional changes within the gammadelta T cell pool in lymph nodes during ageing lead to an unbalanced anti-tumour response. EMBO Rep. 2019;20(8):e47379.PubMedPubMedCentralCrossRef
147.
go back to reference Speiser DE, Ho PC, Verdeil G. Regulatory circuits of T cell function in cancer. Nat Rev Immunol. 2016;16(10):599–611.PubMedCrossRef Speiser DE, Ho PC, Verdeil G. Regulatory circuits of T cell function in cancer. Nat Rev Immunol. 2016;16(10):599–611.PubMedCrossRef
148.
go back to reference Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H. Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res. 2003;9(12):4404–8.PubMed Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H. Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res. 2003;9(12):4404–8.PubMed
149.
go back to reference Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169(5):2756–61.PubMedCrossRef Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169(5):2756–61.PubMedCrossRef
150.
go back to reference Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res. 2005;65(6):2457–64.PubMedCrossRef Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res. 2005;65(6):2457–64.PubMedCrossRef
151.
go back to reference Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, et al. Regulatory CD4 (+) CD25 (+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 2001;61(12):4766–72.PubMed Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, et al. Regulatory CD4 (+) CD25 (+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 2001;61(12):4766–72.PubMed
152.
go back to reference Hou PF, Zhu LJ, Chen XY, Qiu ZQ. Age-related changes in CD4+CD25+FOXP3+ regulatory T cells and their relationship with lung cancer. PLoS One. 2017;12(3):e0173048.PubMedPubMedCentralCrossRef Hou PF, Zhu LJ, Chen XY, Qiu ZQ. Age-related changes in CD4+CD25+FOXP3+ regulatory T cells and their relationship with lung cancer. PLoS One. 2017;12(3):e0173048.PubMedPubMedCentralCrossRef
154.
go back to reference Bent EH, Gilbert LA, Hemann MT. A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses. Genes Dev. 2016;30(16):1811–21.PubMedPubMedCentralCrossRef Bent EH, Gilbert LA, Hemann MT. A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses. Genes Dev. 2016;30(16):1811–21.PubMedPubMedCentralCrossRef
155.
go back to reference Sizova O, Kuriatnikov D, Liu Y, Su DM. Atrophied Thymus, a Tumor Reservoir for Harboring Melanoma Cells. Mol Cancer Res. 2018;16(11):1652–64.PubMedCrossRef Sizova O, Kuriatnikov D, Liu Y, Su DM. Atrophied Thymus, a Tumor Reservoir for Harboring Melanoma Cells. Mol Cancer Res. 2018;16(11):1652–64.PubMedCrossRef
157.
go back to reference Smyth MJ, Dunn GP, Schreiber RD. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol. 2006;90:1–50.PubMedCrossRef Smyth MJ, Dunn GP, Schreiber RD. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol. 2006;90:1–50.PubMedCrossRef
158.
go back to reference Kumari N, Dwarakanath BS, Das A, Bhatt AN. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biol. 2016;37(9):11553–72.PubMedCrossRef Kumari N, Dwarakanath BS, Das A, Bhatt AN. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biol. 2016;37(9):11553–72.PubMedCrossRef
159.
go back to reference Conze D, Weiss L, Regen PS, Bhushan A, Weaver D, Johnson P, et al. Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells. Cancer Res. 2001;61(24):8851–8.PubMed Conze D, Weiss L, Regen PS, Bhushan A, Weaver D, Johnson P, et al. Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells. Cancer Res. 2001;61(24):8851–8.PubMed
160.
go back to reference Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539–45.PubMedCrossRef Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539–45.PubMedCrossRef
162.
go back to reference Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol. 2004;287(1):G7–17.PubMedCrossRef Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol. 2004;287(1):G7–17.PubMedCrossRef
163.
go back to reference Lu H, Ouyang W, Huang C. Inflammation, a key event in cancer development. Mol Cancer Res. 2006;4(4):221–33.PubMedCrossRef Lu H, Ouyang W, Huang C. Inflammation, a key event in cancer development. Mol Cancer Res. 2006;4(4):221–33.PubMedCrossRef
164.
go back to reference Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4(1):71–8.PubMedCrossRef Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4(1):71–8.PubMedCrossRef
165.
go back to reference Hudson JD, Shoaibi MA, Maestro R, Carnero A, Hannon GJ, Beach DH. A proinflammatory cytokine inhibits p53 tumor suppressor activity. J Exp Med. 1999;190(10):1375–82.PubMedPubMedCentralCrossRef Hudson JD, Shoaibi MA, Maestro R, Carnero A, Hannon GJ, Beach DH. A proinflammatory cytokine inhibits p53 tumor suppressor activity. J Exp Med. 1999;190(10):1375–82.PubMedPubMedCentralCrossRef
166.
go back to reference Orosz P, Echtenacher B, Falk W, Ruschoff J, Weber D, Mannel DN. Enhancement of experimental metastasis by tumor necrosis factor. J Exp Med. 1993;177(5):1391–8.PubMedCrossRef Orosz P, Echtenacher B, Falk W, Ruschoff J, Weber D, Mannel DN. Enhancement of experimental metastasis by tumor necrosis factor. J Exp Med. 1993;177(5):1391–8.PubMedCrossRef
167.
go back to reference Orosz P, Kruger A, Hubbe M, Ruschoff J, Von Hoegen P, Mannel DN. Promotion of experimental liver metastasis by tumor necrosis factor. Int J Cancer. 1995;60(6):867–71.PubMedCrossRef Orosz P, Kruger A, Hubbe M, Ruschoff J, Von Hoegen P, Mannel DN. Promotion of experimental liver metastasis by tumor necrosis factor. Int J Cancer. 1995;60(6):867–71.PubMedCrossRef
168.
go back to reference Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer. 2005;41(16):2502–12.PubMedCrossRef Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer. 2005;41(16):2502–12.PubMedCrossRef
169.
go back to reference Wikstrom P, Stattin P, Franck-Lissbrant I, Damber JE, Bergh A. Transforming growth factor beta1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer. Prostate. 1998;37(1):19–29.PubMedCrossRef Wikstrom P, Stattin P, Franck-Lissbrant I, Damber JE, Bergh A. Transforming growth factor beta1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer. Prostate. 1998;37(1):19–29.PubMedCrossRef
170.
go back to reference Pang WW, Price EA, Sahoo D, Beerman I, Maloney WJ, Rossi DJ, et al. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc Natl Acad Sci U S A. 2011;108(50):20012–7.PubMedPubMedCentralCrossRef Pang WW, Price EA, Sahoo D, Beerman I, Maloney WJ, Rossi DJ, et al. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc Natl Acad Sci U S A. 2011;108(50):20012–7.PubMedPubMedCentralCrossRef
171.
go back to reference Morrison SJ, Wandycz AM, Akashi K, Globerson A, Weissman IL. The aging of hematopoietic stem cells. Nat Med. 1996;2(9):1011–6.PubMedCrossRef Morrison SJ, Wandycz AM, Akashi K, Globerson A, Weissman IL. The aging of hematopoietic stem cells. Nat Med. 1996;2(9):1011–6.PubMedCrossRef
172.
go back to reference Waterstrat A, Van Zant G. Effects of aging on hematopoietic stem and progenitor cells. Curr Opin Immunol. 2009;21(4):408–13.PubMedCrossRef Waterstrat A, Van Zant G. Effects of aging on hematopoietic stem and progenitor cells. Curr Opin Immunol. 2009;21(4):408–13.PubMedCrossRef
174.
go back to reference Zhang B, Wang Z, Wu L, Zhang M, Li W, Ding J, et al. Circulating and tumor-infiltrating myeloid-derived suppressor cells in patients with colorectal carcinoma. PLoS One. 2013;8(2):e57114.PubMedPubMedCentralCrossRef Zhang B, Wang Z, Wu L, Zhang M, Li W, Ding J, et al. Circulating and tumor-infiltrating myeloid-derived suppressor cells in patients with colorectal carcinoma. PLoS One. 2013;8(2):e57114.PubMedPubMedCentralCrossRef
175.
176.
go back to reference Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immun. 2018;19(2):108–19.CrossRef Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immun. 2018;19(2):108–19.CrossRef
177.
go back to reference Ruhland MK, Loza AJ, Capietto AH, Luo X, Knolhoff BL, Flanagan KC, et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat Commun. 2016;7:11762.PubMedPubMedCentralCrossRef Ruhland MK, Loza AJ, Capietto AH, Luo X, Knolhoff BL, Flanagan KC, et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat Commun. 2016;7:11762.PubMedPubMedCentralCrossRef
178.
179.
go back to reference Linton PJ, Dorshkind K. Age-related changes in lymphocyte development and function. Nat Immun. 2004;5(2):133–9.CrossRef Linton PJ, Dorshkind K. Age-related changes in lymphocyte development and function. Nat Immun. 2004;5(2):133–9.CrossRef
180.
go back to reference Tyan ML. Age-related decrease in mouse T cell progenitors. J Immunol (Baltimore, Md : 1950). 1977;118(3):846–51. Tyan ML. Age-related decrease in mouse T cell progenitors. J Immunol (Baltimore, Md : 1950). 1977;118(3):846–51.
181.
go back to reference Min H, Montecino-Rodriguez E, Dorshkind K. Effects of aging on early B- and T-cell development. Immunol Rev. 2005;205:7–17.PubMedCrossRef Min H, Montecino-Rodriguez E, Dorshkind K. Effects of aging on early B- and T-cell development. Immunol Rev. 2005;205:7–17.PubMedCrossRef
182.
go back to reference Zhu X, Gui J, Dohkan J, Cheng L, Barnes PF, Su DM. Lymphohematopoietic progenitors do not have a synchronized defect with age-related thymic involution. Aging Cell. 2007;6(5):663–72.PubMedCrossRef Zhu X, Gui J, Dohkan J, Cheng L, Barnes PF, Su DM. Lymphohematopoietic progenitors do not have a synchronized defect with age-related thymic involution. Aging Cell. 2007;6(5):663–72.PubMedCrossRef
183.
go back to reference Peschon JJ, Morrissey PJ, Grabstein KH, Ramsdell FJ, Maraskovsky E, Gliniak BC, et al. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med. 1994;180(5):1955–60.PubMedCrossRef Peschon JJ, Morrissey PJ, Grabstein KH, Ramsdell FJ, Maraskovsky E, Gliniak BC, et al. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med. 1994;180(5):1955–60.PubMedCrossRef
184.
go back to reference Sun L, Hurez VJ, Thibodeaux SR, Kious MJ, Liu A, Lin P, et al. Aged regulatory T cells protect from autoimmune inflammation despite reduced STAT3 activation and decreased constraint of IL-17 producing T cells. Aging Cell. 2012;11(3):509–19.PubMedCrossRef Sun L, Hurez VJ, Thibodeaux SR, Kious MJ, Liu A, Lin P, et al. Aged regulatory T cells protect from autoimmune inflammation despite reduced STAT3 activation and decreased constraint of IL-17 producing T cells. Aging Cell. 2012;11(3):509–19.PubMedCrossRef
185.
go back to reference Porritt HE, Rumfelt LL, Tabrizifard S, Schmitt TM, Zuniga-Pflucker JC, Petrie HT. Heterogeneity among DN1 prothymocytes reveals multiple progenitors with different capacities to generate T cell and non-T cell lineages. Immunity. 2004;20(6):735–45.PubMedCrossRef Porritt HE, Rumfelt LL, Tabrizifard S, Schmitt TM, Zuniga-Pflucker JC, Petrie HT. Heterogeneity among DN1 prothymocytes reveals multiple progenitors with different capacities to generate T cell and non-T cell lineages. Immunity. 2004;20(6):735–45.PubMedCrossRef
186.
187.
go back to reference Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol. 2006;6(2):93–106.PubMedCrossRef Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol. 2006;6(2):93–106.PubMedCrossRef
188.
go back to reference Prockop SE, Petrie HT. Regulation of thymus size by competition for stromal niches among early T cell progenitors. J Immunol. 2004;173(3):1604–11.PubMedCrossRef Prockop SE, Petrie HT. Regulation of thymus size by competition for stromal niches among early T cell progenitors. J Immunol. 2004;173(3):1604–11.PubMedCrossRef
189.
go back to reference Aspinall R, Andrew D. Thymic atrophy in the mouse is a soluble problem of the thymic environment. Vaccine. 2000;18(16):1629–37.PubMedCrossRef Aspinall R, Andrew D. Thymic atrophy in the mouse is a soluble problem of the thymic environment. Vaccine. 2000;18(16):1629–37.PubMedCrossRef
190.
go back to reference Nehls M, Pfeifer D, Schorpp M, Hedrich H, Boehm T. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature. 1994;372(6501):103–7.PubMedCrossRef Nehls M, Pfeifer D, Schorpp M, Hedrich H, Boehm T. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature. 1994;372(6501):103–7.PubMedCrossRef
191.
go back to reference Nehls M, Kyewski B, Messerle M, Waldschutz R, Schuddekopf K, Smith AJ, et al. Two genetically separable steps in the differentiation of thymic epithelium. Science. 1996;272(5263):886–9.PubMedCrossRef Nehls M, Kyewski B, Messerle M, Waldschutz R, Schuddekopf K, Smith AJ, et al. Two genetically separable steps in the differentiation of thymic epithelium. Science. 1996;272(5263):886–9.PubMedCrossRef
193.
go back to reference Brissette JL, Li J, Kamimura J, Lee D, Dotto GP. The product of the mouse nude locus, Whn, regulates the balance between epithelial cell growth and differentiation. Genes Dev. 1996;10(17):2212–21.PubMedCrossRef Brissette JL, Li J, Kamimura J, Lee D, Dotto GP. The product of the mouse nude locus, Whn, regulates the balance between epithelial cell growth and differentiation. Genes Dev. 1996;10(17):2212–21.PubMedCrossRef
194.
go back to reference Flanagan SP. ‘Nude’, a new hairless gene with pleiotropic effects in the mouse. Genet Res. 1966;8(3):295–309.PubMedCrossRef Flanagan SP. ‘Nude’, a new hairless gene with pleiotropic effects in the mouse. Genet Res. 1966;8(3):295–309.PubMedCrossRef
195.
196.
go back to reference Ortman CL, Dittmar KA, Witte PL, Le PT. Molecular characterization of the mouse involuted thymus: aberrations in expression of transcription regulators in thymocyte and epithelial compartments. Int Immunol. 2002;14(7):813–22.PubMedCrossRef Ortman CL, Dittmar KA, Witte PL, Le PT. Molecular characterization of the mouse involuted thymus: aberrations in expression of transcription regulators in thymocyte and epithelial compartments. Int Immunol. 2002;14(7):813–22.PubMedCrossRef
197.
go back to reference Rode I, Martins VC, Kublbeck G, Maltry N, Tessmer C, Rodewald HR. Foxn1 Protein Expression in the Developing, Aging, and Regenerating Thymus. J Immunol. 2015;195(12):5678–87.PubMedCrossRef Rode I, Martins VC, Kublbeck G, Maltry N, Tessmer C, Rodewald HR. Foxn1 Protein Expression in the Developing, Aging, and Regenerating Thymus. J Immunol. 2015;195(12):5678–87.PubMedCrossRef
198.
go back to reference Cheng L, Guo J, Sun L, Fu J, Barnes PF, Metzger D, et al. Postnatal tissue-specific disruption of transcription factor FoxN1 triggers acute thymic atrophy. J Biol Chem. 2010;285(8):5836–47.PubMedCrossRef Cheng L, Guo J, Sun L, Fu J, Barnes PF, Metzger D, et al. Postnatal tissue-specific disruption of transcription factor FoxN1 triggers acute thymic atrophy. J Biol Chem. 2010;285(8):5836–47.PubMedCrossRef
199.
go back to reference Zhang Z, Burnley P, Coder B, Su DM. Insights on FoxN1 biological significance and usages of the “nude” mouse in studies of T-lymphopoiesis. Int J Biol Sci. 2012;8(8):1156–67.PubMedPubMedCentralCrossRef Zhang Z, Burnley P, Coder B, Su DM. Insights on FoxN1 biological significance and usages of the “nude” mouse in studies of T-lymphopoiesis. Int J Biol Sci. 2012;8(8):1156–67.PubMedPubMedCentralCrossRef
200.
201.
go back to reference Bleul CC, Corbeaux T, Reuter A, Fisch P, Monting JS, Boehm T. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature. 2006;441(7096):992–6.PubMedCrossRef Bleul CC, Corbeaux T, Reuter A, Fisch P, Monting JS, Boehm T. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature. 2006;441(7096):992–6.PubMedCrossRef
202.
go back to reference Sun L, Guo J, Brown R, Amagai T, Zhao Y, Su DM. Declining expression of a single epithelial cell-autonomous gene accelerates age-related thymic involution. Aging Cell. 2010;9(3):347–57.PubMedCrossRef Sun L, Guo J, Brown R, Amagai T, Zhao Y, Su DM. Declining expression of a single epithelial cell-autonomous gene accelerates age-related thymic involution. Aging Cell. 2010;9(3):347–57.PubMedCrossRef
203.
go back to reference Zook EC, Krishack PA, Zhang S, Zeleznik-Le NJ, Firulli AB, Witte PL, et al. Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells. Blood. 2011;118(22):5723–31.PubMedPubMedCentralCrossRef Zook EC, Krishack PA, Zhang S, Zeleznik-Le NJ, Firulli AB, Witte PL, et al. Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells. Blood. 2011;118(22):5723–31.PubMedPubMedCentralCrossRef
204.
go back to reference Bredenkamp N, Nowell CS, Blackburn CC. Regeneration of the aged thymus by a single transcription factor. Development (Cambridge, England). 2014;141(8):1627–37.PubMedCentralCrossRef Bredenkamp N, Nowell CS, Blackburn CC. Regeneration of the aged thymus by a single transcription factor. Development (Cambridge, England). 2014;141(8):1627–37.PubMedCentralCrossRef
205.
go back to reference O’Neill KE, Bredenkamp N, Tischner C, Vaidya HJ, Stenhouse FH, Peddie CD, et al. Foxn1 Is Dynamically Regulated in Thymic Epithelial Cells during Embryogenesis and at the Onset of Thymic Involution. PLoS One. 2016;11(3):e0151666.PubMedPubMedCentralCrossRef O’Neill KE, Bredenkamp N, Tischner C, Vaidya HJ, Stenhouse FH, Peddie CD, et al. Foxn1 Is Dynamically Regulated in Thymic Epithelial Cells during Embryogenesis and at the Onset of Thymic Involution. PLoS One. 2016;11(3):e0151666.PubMedPubMedCentralCrossRef
206.
go back to reference Parent AV, Russ HA, Khan IS, LaFlam TN, Metzger TC, Anderson MS, et al. Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development. Cell Stem Cell. 2013;13(2):219–29.PubMedCrossRef Parent AV, Russ HA, Khan IS, LaFlam TN, Metzger TC, Anderson MS, et al. Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development. Cell Stem Cell. 2013;13(2):219–29.PubMedCrossRef
207.
go back to reference Sun X, Xu J, Lu H, Liu W, Miao Z, Sui X, et al. Directed differentiation of human embryonic stem cells into thymic epithelial progenitor-like cells reconstitutes the thymic microenvironment in vivo. Cell Stem Cell. 2013;13(2):230–6.PubMedCrossRef Sun X, Xu J, Lu H, Liu W, Miao Z, Sui X, et al. Directed differentiation of human embryonic stem cells into thymic epithelial progenitor-like cells reconstitutes the thymic microenvironment in vivo. Cell Stem Cell. 2013;13(2):230–6.PubMedCrossRef
208.
go back to reference Soh CL, Giudice A, Jenny RA, Elliott DA, Hatzistavrou T, Micallef SJ, et al. FOXN1 (GFP/w) reporter hESCs enable identification of integrin-beta4, HLA-DR, and EpCAM as markers of human PSC-derived FOXN1(+) thymic epithelial progenitors. Stem Cell Rep. 2014;2(6):925–37.CrossRef Soh CL, Giudice A, Jenny RA, Elliott DA, Hatzistavrou T, Micallef SJ, et al. FOXN1 (GFP/w) reporter hESCs enable identification of integrin-beta4, HLA-DR, and EpCAM as markers of human PSC-derived FOXN1(+) thymic epithelial progenitors. Stem Cell Rep. 2014;2(6):925–37.CrossRef
209.
go back to reference Barsanti M, Lim JM, Hun ML, Lister N, Wong K, Hammett MV, et al. A novel Foxn1(eGFP/+) mouse model identifies Bmp4-induced maintenance of Foxn1 expression and thymic epithelial progenitor populations. Eur J Immunol. 2017;47(2):291–304.PubMedCrossRef Barsanti M, Lim JM, Hun ML, Lister N, Wong K, Hammett MV, et al. A novel Foxn1(eGFP/+) mouse model identifies Bmp4-induced maintenance of Foxn1 expression and thymic epithelial progenitor populations. Eur J Immunol. 2017;47(2):291–304.PubMedCrossRef
210.
go back to reference Kim MJ, Miller CM, Shadrach JL, Wagers AJ, Serwold T. Young, proliferative thymic epithelial cells engraft and function in aging thymuses. J Immunol (Baltimore, Md : 1950). 2015;194(10):4784–95.CrossRef Kim MJ, Miller CM, Shadrach JL, Wagers AJ, Serwold T. Young, proliferative thymic epithelial cells engraft and function in aging thymuses. J Immunol (Baltimore, Md : 1950). 2015;194(10):4784–95.CrossRef
211.
go back to reference Bredenkamp N, Ulyanchenko S, O'Neill KE, Manley NR, Vaidya HJ, Blackburn CC. An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts. Nat Cell Biol. 2014;16(9):902–8.PubMedPubMedCentralCrossRef Bredenkamp N, Ulyanchenko S, O'Neill KE, Manley NR, Vaidya HJ, Blackburn CC. An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts. Nat Cell Biol. 2014;16(9):902–8.PubMedPubMedCentralCrossRef
212.
go back to reference Erickson M, Morkowski S, Lehar S, Gillard G, Beers C, Dooley J, et al. Regulation of thymic epithelium by keratinocyte growth factor. Blood. 2002;100(9):3269–78.PubMedCrossRef Erickson M, Morkowski S, Lehar S, Gillard G, Beers C, Dooley J, et al. Regulation of thymic epithelium by keratinocyte growth factor. Blood. 2002;100(9):3269–78.PubMedCrossRef
213.
go back to reference Alpdogan O, Hubbard VM, Smith OM, Patel N, Lu S, Goldberg GL, et al. Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration. Blood. 2006;107(6):2453–60.PubMedPubMedCentralCrossRef Alpdogan O, Hubbard VM, Smith OM, Patel N, Lu S, Goldberg GL, et al. Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration. Blood. 2006;107(6):2453–60.PubMedPubMedCentralCrossRef
215.
go back to reference Dudakov JA, Hanash AM, Jenq RR, Young LF, Ghosh A, Singer NV, et al. Interleukin-22 drives endogenous thymic regeneration in mice. Science. 2012;336(6077):91–5.PubMedPubMedCentralCrossRef Dudakov JA, Hanash AM, Jenq RR, Young LF, Ghosh A, Singer NV, et al. Interleukin-22 drives endogenous thymic regeneration in mice. Science. 2012;336(6077):91–5.PubMedPubMedCentralCrossRef
217.
go back to reference Pan B, Liu J, Zhang Y, Sun Y, Wu Q, Zhao K, et al. Acute ablation of DP thymocytes induces up-regulation of IL-22 and Foxn1 in TECs. Clin Immunol (Orlando, Fla). 2014;150(1):101–8.CrossRef Pan B, Liu J, Zhang Y, Sun Y, Wu Q, Zhao K, et al. Acute ablation of DP thymocytes induces up-regulation of IL-22 and Foxn1 in TECs. Clin Immunol (Orlando, Fla). 2014;150(1):101–8.CrossRef
218.
go back to reference Okoye AA, Rohankhedkar M, Konfe AL, Abana CO, Reyes MD, Clock JA, et al. Effect of IL-7 Therapy on Naive and Memory T Cell Homeostasis in Aged Rhesus Macaques. J Immunol (Baltimore, Md : 1950). 2015;195(9):4292–305.CrossRef Okoye AA, Rohankhedkar M, Konfe AL, Abana CO, Reyes MD, Clock JA, et al. Effect of IL-7 Therapy on Naive and Memory T Cell Homeostasis in Aged Rhesus Macaques. J Immunol (Baltimore, Md : 1950). 2015;195(9):4292–305.CrossRef
220.
go back to reference Henson SM, Snelgrove R, Hussell T, Wells DJ, Aspinall R. An IL-7 fusion protein that shows increased thymopoietic ability. J Immunol (Baltimore, Md : 1950). 2005;175(6):4112–8.CrossRef Henson SM, Snelgrove R, Hussell T, Wells DJ, Aspinall R. An IL-7 fusion protein that shows increased thymopoietic ability. J Immunol (Baltimore, Md : 1950). 2005;175(6):4112–8.CrossRef
221.
go back to reference Perales MA, Goldberg JD, Yuan J, Koehne G, Lechner L, Papadopoulos EB, et al. Recombinant human interleukin-7 (CYT107) promotes T-cell recovery after allogeneic stem cell transplantation. Blood. 2012;120(24):4882–91.PubMedPubMedCentralCrossRef Perales MA, Goldberg JD, Yuan J, Koehne G, Lechner L, Papadopoulos EB, et al. Recombinant human interleukin-7 (CYT107) promotes T-cell recovery after allogeneic stem cell transplantation. Blood. 2012;120(24):4882–91.PubMedPubMedCentralCrossRef
222.
go back to reference Savino W, Postel-Vinay MC, Smaniotto S, Dardenne M. The thymus gland: a target organ for growth hormone. Scand J Immunol. 2002;55(5):442–52.PubMedCrossRef Savino W, Postel-Vinay MC, Smaniotto S, Dardenne M. The thymus gland: a target organ for growth hormone. Scand J Immunol. 2002;55(5):442–52.PubMedCrossRef
223.
go back to reference Hirokawa K, Utsuyama M, Kikuchi Y. Trade off situation between thymus and growth hormone: age-related decline of growth hormone is a cause of thymic involution but favorable for elongation of lifespan. Biogerontology. 2016;17(1):55–9.PubMedCrossRef Hirokawa K, Utsuyama M, Kikuchi Y. Trade off situation between thymus and growth hormone: age-related decline of growth hormone is a cause of thymic involution but favorable for elongation of lifespan. Biogerontology. 2016;17(1):55–9.PubMedCrossRef
224.
go back to reference Chen BJ, Cui X, Sempowski GD, Chao NJ. Growth hormone accelerates immune recovery following allogeneic T-cell-depleted bone marrow transplantation in mice. Exp Hematol. 2003;31(10):953–8.PubMedCrossRef Chen BJ, Cui X, Sempowski GD, Chao NJ. Growth hormone accelerates immune recovery following allogeneic T-cell-depleted bone marrow transplantation in mice. Exp Hematol. 2003;31(10):953–8.PubMedCrossRef
225.
go back to reference De Mello-Coelho V, Savino W, Postel-Vinay MC, Dardenne M. Role of prolactin and growth hormone on thymus physiology. Dev Immunol. 1998;6(3-4):317–23.PubMedPubMedCentralCrossRef De Mello-Coelho V, Savino W, Postel-Vinay MC, Dardenne M. Role of prolactin and growth hormone on thymus physiology. Dev Immunol. 1998;6(3-4):317–23.PubMedPubMedCentralCrossRef
226.
go back to reference Geenen V, Achour I, Robert F, Vandersmissen E, Sodoyez JC, Defresne MP, et al. Evidence that insulin-like growth factor 2 (IGF2) is the dominant thymic peptide of the insulin superfamily. Thymus. 1993;21(2):115–27.PubMed Geenen V, Achour I, Robert F, Vandersmissen E, Sodoyez JC, Defresne MP, et al. Evidence that insulin-like growth factor 2 (IGF2) is the dominant thymic peptide of the insulin superfamily. Thymus. 1993;21(2):115–27.PubMed
227.
go back to reference Ban E, Gagnerault MC, Jammes H, Postel-Vinay MC, Haour F, Dardenne M. Specific binding sites for growth hormone in cultured mouse thymic epithelial cells. Life Sci. 1991;48(22):2141–8.PubMedCrossRef Ban E, Gagnerault MC, Jammes H, Postel-Vinay MC, Haour F, Dardenne M. Specific binding sites for growth hormone in cultured mouse thymic epithelial cells. Life Sci. 1991;48(22):2141–8.PubMedCrossRef
228.
go back to reference Savino W, Mendes-da-Cruz DA, Lepletier A, Dardenne M. Hormonal control of T-cell development in health and disease. Nat Rev Endocrinol. 2016;12(2):77–89.PubMedCrossRef Savino W, Mendes-da-Cruz DA, Lepletier A, Dardenne M. Hormonal control of T-cell development in health and disease. Nat Rev Endocrinol. 2016;12(2):77–89.PubMedCrossRef
229.
go back to reference Paton DN. The relationship of the thymus to the sexual organs: II. The influence of removal of the thymus on the growth of the sexual organs. J Physiol. 1904;32(1):28–32.PubMedPubMedCentralCrossRef Paton DN. The relationship of the thymus to the sexual organs: II. The influence of removal of the thymus on the growth of the sexual organs. J Physiol. 1904;32(1):28–32.PubMedPubMedCentralCrossRef
230.
go back to reference Heng TS, Goldberg GL, Gray DH, Sutherland JS, Chidgey AP, Boyd RL. Effects of castration on thymocyte development in two different models of thymic involution. J Immunol. 2005;175(5):2982–93.PubMedCrossRef Heng TS, Goldberg GL, Gray DH, Sutherland JS, Chidgey AP, Boyd RL. Effects of castration on thymocyte development in two different models of thymic involution. J Immunol. 2005;175(5):2982–93.PubMedCrossRef
231.
go back to reference Sutherland JS, Goldberg GL, Hammett MV, Uldrich AP, Berzins SP, Heng TS, et al. Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol. 2005;175(4):2741–53.PubMedCrossRef Sutherland JS, Goldberg GL, Hammett MV, Uldrich AP, Berzins SP, Heng TS, et al. Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol. 2005;175(4):2741–53.PubMedCrossRef
232.
go back to reference Goldberg GL, Sutherland JS, Hammet MV, Milton MK, Heng TS, Chidgey AP, et al. Sex steroid ablation enhances lymphoid recovery following autologous hematopoietic stem cell transplantation. Transplantation. 2005;80(11):1604–13.PubMedCrossRef Goldberg GL, Sutherland JS, Hammet MV, Milton MK, Heng TS, Chidgey AP, et al. Sex steroid ablation enhances lymphoid recovery following autologous hematopoietic stem cell transplantation. Transplantation. 2005;80(11):1604–13.PubMedCrossRef
233.
go back to reference Gray DH, Seach N, Ueno T, Milton MK, Liston A, Lew AM, et al. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood. 2006;108(12):3777–85.PubMedCrossRef Gray DH, Seach N, Ueno T, Milton MK, Liston A, Lew AM, et al. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood. 2006;108(12):3777–85.PubMedCrossRef
234.
go back to reference Olsen NJ, Olson G, Viselli SM, Gu X, Kovacs WJ. Androgen receptors in thymic epithelium modulate thymus size and thymocyte development. Endocrinology. 2001;142(3):1278–83.PubMedCrossRef Olsen NJ, Olson G, Viselli SM, Gu X, Kovacs WJ. Androgen receptors in thymic epithelium modulate thymus size and thymocyte development. Endocrinology. 2001;142(3):1278–83.PubMedCrossRef
235.
go back to reference Velardi E, Tsai JJ, Holland AM, Wertheimer T, Yu VW, Zakrzewski JL, et al. Sex steroid blockade enhances thymopoiesis by modulating Notch signaling. J Exp Med. 2014;211(12):2341–9.PubMedPubMedCentralCrossRef Velardi E, Tsai JJ, Holland AM, Wertheimer T, Yu VW, Zakrzewski JL, et al. Sex steroid blockade enhances thymopoiesis by modulating Notch signaling. J Exp Med. 2014;211(12):2341–9.PubMedPubMedCentralCrossRef
236.
go back to reference Min H, Montecino-Rodriguez E, Dorshkind K. Reassessing the role of growth hormone and sex steroids in thymic involution. Clin Immunol. 2006;118(1):117–23.PubMedCrossRef Min H, Montecino-Rodriguez E, Dorshkind K. Reassessing the role of growth hormone and sex steroids in thymic involution. Clin Immunol. 2006;118(1):117–23.PubMedCrossRef
237.
go back to reference Griffith AV, Fallahi M, Venables T, Petrie HT. Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth. Aging Cell. 2012;11(1):169–77.PubMedCrossRef Griffith AV, Fallahi M, Venables T, Petrie HT. Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth. Aging Cell. 2012;11(1):169–77.PubMedCrossRef
238.
go back to reference Page ST, Plymate SR, Bremner WJ, Matsumoto AM, Hess DL, Lin DW, et al. Effect of medical castration on CD4+ CD25+ T cells, CD8+ T cell IFN-gamma expression, and NK cells: a physiological role for testosterone and/or its metabolites. Am J Physiol Endocrinol Metab. 2006;290(5):E856–63.PubMedCrossRef Page ST, Plymate SR, Bremner WJ, Matsumoto AM, Hess DL, Lin DW, et al. Effect of medical castration on CD4+ CD25+ T cells, CD8+ T cell IFN-gamma expression, and NK cells: a physiological role for testosterone and/or its metabolites. Am J Physiol Endocrinol Metab. 2006;290(5):E856–63.PubMedCrossRef
239.
go back to reference Brown MA, Su MA. An Inconvenient Variable: Sex Hormones and Their Impact on T Cell Responses. J Immunol. 2019;202(7):1927–33.PubMedCrossRef Brown MA, Su MA. An Inconvenient Variable: Sex Hormones and Their Impact on T Cell Responses. J Immunol. 2019;202(7):1927–33.PubMedCrossRef
241.
go back to reference Dragin N, Bismuth J, Cizeron-Clairac G, Biferi MG, Berthault C, Serraf A, et al. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. J Clin Invest. 2016;126(4):1525–37.PubMedPubMedCentralCrossRef Dragin N, Bismuth J, Cizeron-Clairac G, Biferi MG, Berthault C, Serraf A, et al. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. J Clin Invest. 2016;126(4):1525–37.PubMedPubMedCentralCrossRef
242.
go back to reference Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature. 2005;433(7027):760–4.PubMedCrossRef Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature. 2005;433(7027):760–4.PubMedCrossRef
243.
go back to reference Pishel I, Shytikov D, Orlova T, Peregudov A, Artyuhov I, Butenko G. Accelerated aging versus rejuvenation of the immune system in heterochronic parabiosis. Rejuvenation Res. 2012;15(2):239–48.PubMedCrossRef Pishel I, Shytikov D, Orlova T, Peregudov A, Artyuhov I, Butenko G. Accelerated aging versus rejuvenation of the immune system in heterochronic parabiosis. Rejuvenation Res. 2012;15(2):239–48.PubMedCrossRef
244.
go back to reference Ruckh JM, Zhao JW, Shadrach JL, van Wijngaarden P, Rao TN, Wagers AJ, et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell. 2012;10(1):96–103.PubMedPubMedCentralCrossRef Ruckh JM, Zhao JW, Shadrach JL, van Wijngaarden P, Rao TN, Wagers AJ, et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell. 2012;10(1):96–103.PubMedPubMedCentralCrossRef
245.
go back to reference Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C, et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science. 2007;317(5839):807–10.PubMedCrossRef Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C, et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science. 2007;317(5839):807–10.PubMedCrossRef
246.
go back to reference Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P, et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell. 2013;153(4):828–39.PubMedPubMedCentralCrossRef Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P, et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell. 2013;153(4):828–39.PubMedPubMedCentralCrossRef
247.
go back to reference Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014;344(6184):630–4.PubMedPubMedCentralCrossRef Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014;344(6184):630–4.PubMedPubMedCentralCrossRef
248.
go back to reference Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014;20(6):659–63.PubMedPubMedCentralCrossRef Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014;20(6):659–63.PubMedPubMedCentralCrossRef
249.
go back to reference Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477(7362):90–4.PubMedPubMedCentralCrossRef Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477(7362):90–4.PubMedPubMedCentralCrossRef
250.
go back to reference Villeda SA, Wyss-Coray T. The circulatory systemic environment as a modulator of neurogenesis and brain aging. Autoimmun Rev. 2013;12(6):674–7.PubMedCrossRef Villeda SA, Wyss-Coray T. The circulatory systemic environment as a modulator of neurogenesis and brain aging. Autoimmun Rev. 2013;12(6):674–7.PubMedCrossRef
251.
go back to reference Wang W, Wang L, Ruan L, Oh J, Dong X, Zhuge Q, et al. Extracellular vesicles extracted from young donor serum attenuate inflammaging via partially rejuvenating aged T-cell immunotolerance. FASEB J. 2018;1:fj201800059R. Wang W, Wang L, Ruan L, Oh J, Dong X, Zhuge Q, et al. Extracellular vesicles extracted from young donor serum attenuate inflammaging via partially rejuvenating aged T-cell immunotolerance. FASEB J. 2018;1:fj201800059R.
252.
go back to reference Araki T, Nishino M, Gao W, Dupuis J, Hunninghake GM, Murakami T, et al. Normal thymus in adults: appearance on CT and associations with age, sex, BMI and smoking. Eur Radiol. 2016;26(1):15–24.PubMedCrossRef Araki T, Nishino M, Gao W, Dupuis J, Hunninghake GM, Murakami T, et al. Normal thymus in adults: appearance on CT and associations with age, sex, BMI and smoking. Eur Radiol. 2016;26(1):15–24.PubMedCrossRef
253.
go back to reference Duggal NA, Pollock RD, Lazarus NR, Harridge S, Lord JM. Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood. Aging Cell. 2018;17:2.CrossRef Duggal NA, Pollock RD, Lazarus NR, Harridge S, Lord JM. Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood. Aging Cell. 2018;17:2.CrossRef
254.
go back to reference Duggal NA, Niemiro G, Harridge SDR, Simpson RJ, Lord JM. Can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity? Nat Rev Immunol. 2019;19(9):563–72.PubMedCrossRef Duggal NA, Niemiro G, Harridge SDR, Simpson RJ, Lord JM. Can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity? Nat Rev Immunol. 2019;19(9):563–72.PubMedCrossRef
Metadata
Title
Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging
Authors
Rachel Thomas
Weikan Wang
Dong-Ming Su
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Immunity & Ageing / Issue 1/2020
Electronic ISSN: 1742-4933
DOI
https://doi.org/10.1186/s12979-020-0173-8

Other articles of this Issue 1/2020

Immunity & Ageing 1/2020 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine