The immune system of an organism is an essential component of the defense mechanism aimed at combating pathogenic stress. Age-associated immune dysfunction, also dubbed “immune senescence,” manifests as increased susceptibility to infections, increased onset and progression of autoimmune diseases, and onset of neoplasia. Over the years, extensive research has generated consensus in terms of the phenotypic and functional defects within the immune system in various organisms, including humans. Indeed, age-associated alterations such as thymic involution, T cell repertoire skewing, decreased ability to activate naïve T cells and to generate robust memory responses, have been shown to have a causative role in immune decline. Further, understanding the molecular mechanisms underlying the generation of proteotoxic stress, DNA damage response, modulation of ubiquitin proteasome pathway, and regulation of transcription factor NFκB activation, in immune decline, have paved the way to delineating signaling pathways that cross-talk and impact immune senescence. Given the role of the immune system in combating infections, its effectiveness with age may well be a marker of health and a predictor of longevity. It is therefore believed that a better understanding of the mechanisms underlying immune senescence will lead to an effective interventional strategy aimed at improving the health span of individuals. Antioxid. Redox Signal. 14, 1551–1585.
AdolfssonO, HuberBT, MeydaniSN. Vitamin E-enhanced IL-2 production in old mice: naive but not memory T cells show increased cell division cycling and IL-2-producing capacity. J Immunol, 167:3809–3817. 2001.
4.
AgrawalA, AgrawalS, CaoJN, SuH, OsannK, GuptaS. Altered innate immune functioning of dendritic cells in elderly humans: a role of phosphoinositide 3-kinase-signaling pathway. J Immunol, 178:6912–6922. 2007.
5.
AkiyamaM, YamadaO, HideshimaT, YanagisawaT, YokoiK, FujisawaK, EtoY, YamadaH, AndersonKC. TNFalpha induces rapid activation and nuclear translocation of telomerase in human lymphocytes. Biochem Biophys Res Commun, 316:528–532. 2004.
6.
AlbertiS, CeveniniE, OstanR, CapriM, SalvioliS, BucciL, GinaldiL, DeMM, FranceschiC, MontiD. Age-dependent modifications of type 1 and type 2 cytokines within virgin and memory CD4+ T cells in humans. Mech Ageing Dev, 127:560–566. 2006.
7.
AlmanzarG, SchwaigerS, JeneweinB, KellerM, Herndler-BrandstetterD, WurznerR, SchonitzerD, Grubeck-LoebensteinB. Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons. J Virol, 79:3675–3683. 2005.
8.
AlpdoganO, HubbardVM, SmithOM, PatelN, LuS, GoldbergGL, GrayDH, FeinmanJ, KochmanAA, EngJM, SuhD, MuriglanSJ, BoydRL, van den BrinkMR. Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration. Blood, 107:2453–2460. 2006.
9.
AlvarezE, Ruiz-GutierrezV, SobrinoF, Santa-MariaC. Age-related changes in membrane lipid composition, fluidity and respiratory burst in rat peritoneal neutrophils. Clin Exp Immunol, 124:95–102. 2001.
10.
AlvesNL, HuntingtonND, RodewaldHR, Di SantoJP. Thymic epithelial cells: the multi-tasking framework of the T cell “cradle.”Trends Immunol, 30:468–474. 2009.
11.
AndrewD, AspinallR. Il-7 and not stem cell factor reverses both the increase in apoptosis and the decline in thymopoiesis seen in aged mice. J Immunol, 166:1524–1530. 2001.
12.
AndrewsNP, FujiiH, GoronzyJJ, WeyandCM. Telomeres and immunological diseases of aging. Gerontology, 56:390–403. 2010.
ArmaniosM. Syndromes of telomere shortening. Annu Rev Genomics Hum Genet, 10:45–61. 2009.
15.
ArmaniosM, AlderJK, ParryEM, KarimB, StrongMA, GreiderCW. Short telomeres are sufficient to cause the degenerative defects associated with aging. Am J Hum Genet, 85:823–832. 2009.
16.
AspinallR, Pido-LopezJ, ImamiN, HensonSM, NgomPT, MorreM, NiphuisH, RemarqueE, RosenwirthB, HeeneyJL. Old rhesus macaques treated with interleukin-7 show increased TREC levels and respond well to influenza vaccination. Rejuvenation Res, 10:5–17. 2007.
17.
AspinallR, PittsD, LapennaA, MitchellW. Immunity in the elderly: the role of the thymus. J Comp Pathol, 142:S111–S115. 2010.
18.
AtamnaH, Paler-MartinezA, AmesBN. N-t-butyl hydroxylamine, a hydrolysis product of alpha-phenyl-N-t-butyl nitrone, is more potent in delaying senescence in human lung fibroblasts. J Biol Chem, 275:6741–6748. 2000.
19.
AvivA, ChenW, GardnerJP, KimuraM, BrimacombeM, CaoX, SrinivasanSR, BerensonGS. Leukocyte telomere dynamics: longitudinal findings among young adults in the Bogalusa Heart Study. Am J Epidemiol, 169:323–329. 2009.
20.
AwD, SilvaAB, PalmerDB. Immunosenescence: emerging challenges for an ageing population. Immunology, 120:435–446. 2007.
21.
AwD, SilvaAB, PalmerDB. The effect of age on the phenotype and function of developing thymocytes. J Comp Pathol, 142:S45–S59. 2010.
BassingCH, AltFW. The cellular response to general and programmed DNA double strand breaks. DNA Repair (Amst), 3:781–796. 2004.
24.
BauerS, MullerT, HammS. Pattern recognition by toll-like receptors. Adv Exp Med Biol, 653:15–34. 2009.
25.
Ben-ZviA, MillerEA, MorimotoRI. Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging. Proc Natl Acad Sci U S A, 106:14914–14919. 2009.
26.
BhushanM, CumberbatchM, DearmanRJ, AndrewSM, KimberI, GriffithsCE. Tumour necrosis factor-alpha-induced migration of human Langerhans cells: the influence of ageing. Br J Dermatol, 146:32–40. 2002.
27.
BiasiD, CarlettoA, Dell'AgnolaC, CaramaschiP, MontesantiF, ZavateriG, ZeminianS, BellaviteP, BambaraLM. Neutrophil migration, oxidative metabolism, and adhesion in elderly and young subjects. Inflammation, 20:673–681. 1996.
28.
BlagosklonnyMV. Aging: ROS or TOR. Cell Cycle, 7:3344–3354. 2008.
BoyaultC, ZhangY, FritahS, CaronC, GilquinB, KwonSH, GarridoC, YaoTP, Vourc'hC, MatthiasP, KhochbinS. HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates. Genes Dev, 21:2172–2181. 2007.
33.
BrackC, Bechter-ThuringE, LabuhnM. N-acetylcysteine slows down ageing and increases the life span of Drosophila melanogaster. Cell Mol Life Sci, 53:960–966. 1997.
34.
BruinsmaM, van SoestPL, LeenenPJ, LambrechtBN, CupedoT, LowenbergB, CornelissenJJ, BraakmanE. Keratinocyte growth factor induces expansion of murine peripheral CD4+Foxp3+ regulatory T cells and increases their thymic output. J Immunol, 179:7424–7430. 2007.
35.
BrunkUT, TermanA. Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radic Biol Med, 33:611–619. 2002.
36.
BruunsgaardH, ndersen-RanbergK, HjelmborgJB, PedersenBK, JeuneB. Elevated levels of tumor necrosis factor alpha and mortality in centenarians. Am J Med, 115:278–283. 2003.
37.
BuchkovichKJ, GreiderCW. Telomerase regulation during entry into the cell cycle in normal human T cells. Mol Biol Cell, 7:1443–1454. 1996.
38.
CalderwoodSK, MurshidA, PrinceT. The shock of aging: molecular chaperones and the heat shock response in longevity and aging—a mini-review. Gerontology, 55:550–558. 2009.
39.
CaligiuriMA. Human natural killer cells. Blood, 112:461–469. 2008.
40.
CancroMP, HaoY, ScholzJL, RileyRL, FrascaD, Dunn-WaltersDK, BlombergBB. B cells and aging: molecules and mechanisms. Trends Immunol, 30:313–318. 2009.
41.
CaoW, ManicassamyS, TangH, KasturiSP, PiraniA, MurthyN, PulendranB. Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nat Immunol, 9:1157–1164. 2008.
42.
CarlinLM, YanagiK, VerhoefA, Nolte-'t HoenEN, YatesJ, GardnerL, LambJ, LombardiG, DallmanMJ, DavisDM. Secretion of IFN-gamma and not IL-2 by anergic human T cells correlates with assembly of an immature immune synapse. Blood, 106:3874–3879. 2005.
43.
CarneyJM, Starke-ReedPE, OliverCN, LandumRW, ChengMS, WuJF, FloydRA. Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone. Proc Natl Acad Sci U S A, 88:3633–3636. 1991.
44.
CarranoAC, LiuZ, DillinA, HunterT. A conserved ubiquitination pathway determines longevity in response to diet restriction. Nature, 460:396–399. 2009.
45.
CasillasMAJr., LopatinaN, AndrewsLG, TollefsbolTO. Transcriptional control of the DNA methyltransferases is altered in aging and neoplastically-transformed human fibroblasts. Mol Cell Biochem, 252:33–43. 2003.
46.
CemerskiS, CantagrelA, van MeerwijkJP, RomagnoliP. Reactive oxygen species differentially affect T cell receptor-signaling pathways. J Biol Chem, 277:19585–19593. 2002.
47.
CemerskiS, van MeerwijkJP, RomagnoliP. Oxidative-stress-induced T lymphocyte hyporesponsiveness is caused by structural modification rather than proteasomal degradation of crucial TCR signaling molecules. Eur J Immunol, 33:2178–2185. 2003.
ChangKT, MinKT. Regulation of lifespan by histone deacetylase. Ageing Res Rev, 1:313–326. 2002.
50.
ChattaGS, AndrewsRG, RodgerE, SchragM, HammondWP, DaleDC. Hematopoietic progenitors and aging: alterations in granulocytic precursors and responsiveness to recombinant human G-CSF, GM-CSF, and IL-3. J Gerontol, 48:M207–M212. 1993.
51.
ChavesMM, CostaDC, PereiraCC, AndradeTR, HortaBC, Nogueira-MachadoJA. Role of inositol 1,4,5-triphosphate and p38 mitogen-activated protein kinase in reactive oxygen species generation by granulocytes in a cyclic AMP-dependent manner: an age-related phenomenon. Gerontology, 53:228–233. 2007.
ChondrogianniN, TzavelasC, PembertonAJ, NezisIP, RivettAJ, GonosES. Overexpression of proteasome beta5 assembled subunit increases the amount of proteasome and confers ameliorated response to oxidative stress and higher survival rates. J Biol Chem, 280:11840–11850. 2005.
54.
ChungHY, CesariM, AntonS, MarzettiE, GiovanniniS, SeoAY, CarterC, YuBP, LeeuwenburghC. Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res Rev, 8:18–30. 2009.
55.
ChungHY, KimHJ, KimKW, ChoiJS, YuBP. Molecular inflammation hypothesis of aging based on the anti-aging mechanism of calorie restriction. Microsc Res Tech, 59:264–272. 2002.
56.
ChungHY, SungB, JungKJ, ZouY, YuBP. The molecular inflammatory process in aging. Antioxid Redox Signal, 8:572–581. 2006.
57.
CiechanoverA. Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat Rev Mol Cell Biol, 6:79–87. 2005.
Clise-DwyerK, HustonGE, BuckAL, DusoDK, SwainSL. Environmental and intrinsic factors lead to antigen unresponsiveness in CD4(+) recent thymic emigrants from aged mice. J Immunol, 178:1321–1331. 2007.
60.
CorcoranLM. Transcriptional control of B cell activation. Curr Top Microbiol Immunol, 290:105–146. 2005.
61.
CsiszarA, LabinskyyN, JimenezR, PintoJT, BallabhP, LosonczyG, PearsonKJ, deCR, UngvariZ. Anti-oxidative and anti-inflammatory vasoprotective effects of caloric restriction in aging: role of circulating factors and SIRT1. Mech Ageing Dev, 130:518–527. 2009.
62.
CuervoAM. Autophagy and aging: keeping that old broom working. Trends Genet, 24:604–612. 2008.
63.
CuervoAM, BergaminiE, BrunkUT, DrogeW, FfrenchM, TermanA. Autophagy and aging: the importance of maintaining “clean” cells. Autophagy, 1:131–140. 2005.
64.
CuervoAM, DiceJF. A receptor for the selective uptake and degradation of proteins by lysosomes. Science, 273:501–503. 1996.
CullenSJ, PonnappanS, PonnappanU. Proteasome inhibition up-regulates inflammatory gene transcription induced by an atypical pathway of NF-kappaB activation. Biochem Pharmacol, 79:706–714. 2010.
67.
CurtaleG, CitarellaF, CarissimiC, GoldoniM, CarucciN, FulciV, FranceschiniD, MeloniF, BarnabaV, MacinoG. An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and AICD in T lymphocytes. Blood, 115:265–273. 2010.
68.
d'Adda diFF, ReaperPM, Clay-FarraceL, FieglerH, CarrP, VonZT, SaretzkiG, CarterNP, JacksonSP. A DNA damage checkpoint response in telomere-initiated senescence. Nature, 426:194–198. 2003.
69.
DahlmannB. Role of proteasomes in disease. BMC Biochem, 8,Suppl 1:S3. 2007.
70.
DantumaNP, LindstenK. Stressing the ubiquitin-proteasome system. Cardiovasc Res, 85:263–271. 2010.
71.
DasR, PonnappanS, PonnappanU. Redox regulation of the proteasome in T lymphocytes during aging. Free Radic Biol Med, 42:541–551. 2007.
72.
DavenportMP, PriceDA, McMichaelAJ. The T cell repertoire in infection and vaccination: implications for control of persistent viruses. Curr Opin Immunol, 19:294–300. 2007.
73.
De BenedictisG, FranceschiC. The unusual genetics of human longevity. Sci Aging Knowledge Environ, 2006:e20. 2006.
74.
de BoerJ, AndressooJO, deWJ, HuijmansJ, BeemsRB, vanSH, WeedaG, van der HorstGT, vanLW, ThemmenAP, MeradjiM, HoeijmakersJH. Premature aging in mice deficient in DNA repair and transcription. Science, 296:1276–1279. 2002.
75.
de MagalhaesJP, CuradoJ, ChurchGM. Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics, 25:875–881. 2009.
76.
De MartinisM, FranceschiC, MontiD, GinaldiL. Inflammation markers predicting frailty and mortality in the elderly. Exp Mol Pathol, 80:219–227. 2006.
77.
DelaRosaO, TarazonaR, CasadoJG, AlonsoC, OstosB, PenaJ, SolanaR. Valpha24+ NKT cells are decreased in elderly humans. Exp Gerontol, 37:213–217. 2002.
78.
DellaBS, BiertiL, PresicceP, ArientiR, ValentiM, SaresellaM, VerganiC, VillaML. Peripheral blood dendritic cells and monocytes are differently regulated in the elderly. Clin Immunol, 122:220–228. 2007.
79.
DelpedroAD, BarjavelMJ, MamdouhZ, FaureS, BakoucheO. Signal transduction in LPS-activated aged and young monocytes. J Interferon Cytokine Res, 18:429–437. 1998.
80.
DengjelJ, SchoorO, FischerR, ReichM, KrausM, MullerM, KreymborgK, AltenberendF, BrandenburgJ, KalbacherH, BrockR, DriessenC, RammenseeHG, StevanovicS. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc Natl Acad Sci U S A, 102:7922–7927. 2005.
81.
DiceJF. Peptide sequences that target cytosolic proteins for lysosomal proteolysis. Trends Biochem Sci, 15:305–309. 1990.
82.
DiehnM, ChoRW, LoboNA, KaliskyT, DorieMJ, KulpAN, QianD, LamJS, AillesLE, WongM, JoshuaB, KaplanMJ, WapnirI, DirbasFM, SomloG, GarberoglioC, PazB, ShenJ, LauSK, QuakeSR, BrownJM, WeissmanIL, ClarkeMF. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature, 458:780–783. 2009.
83.
DixitVD, TaubDD. Ghrelin and immunity: a young player in an old field. Exp Gerontol, 40:900–910. 2005.
84.
DixitVD, YangH, Cooper-JenkinsA, GiriBB, PatelK, TaubDD. Reduction of T cell-derived ghrelin enhances proinflammatory cytokine expression: implications for age-associated increases in inflammation. Blood, 113:5202–5205. 2009.
DorshkindK, Montecino-RodriguezE, SignerRA. The ageing immune system: is it ever too old to become young again?Nat Rev Immunol, 9:57–62. 2009.
87.
DouekDC, McFarlandRD, KeiserPH, GageEA, MasseyJM, HaynesBF, PolisMA, HaaseAT, FeinbergMB, SullivanJL, JamiesonBD, ZackJA, PickerLJ, KoupRA. Changes in thymic function with age and during the treatment of HIV infection. Nature, 396:690–695. 1998.
EisenbraunMD, TamirA, MillerRA. Altered composition of the immunological synapse in an anergic, age-dependent memory T cell subset. J Immunol, 164:6105–6112. 2000.
90.
EnckP, ZimmermannK, RuschK, SchwiertzA, KlosterhalfenS, FrickJS. The effects of ageing on the colonic bacterial microflora in adults. Z Gastroenterol, 47:653–658. 2009.
91.
ErikssonM, BrownWT, GordonLB, GlynnMW, SingerJ, ScottL, ErdosMR, RobbinsCM, MosesTY, BerglundP, DutraA, PakE, DurkinS, CsokaAB, BoehnkeM, GloverTW, CollinsFS. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature, 423:293–298. 2003.
92.
ErmakG, DaviesKJ. Calcium and oxidative stress: from cell signaling to cell death. Mol Immunol, 38:713–721. 2002.
93.
ErshlerWB, KellerET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med, 51:245–270. 2000.
94.
FauceSR, JamiesonBD, ChinAC, MitsuyasuRT, ParishST, NgHL, KitchenCM, YangOO, HarleyCB, EffrosRB. Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes. J Immunol, 181:7400–7406. 2008.
95.
FeinbergAP, OhlssonR, HenikoffS. The epigenetic progenitor origin of human cancer. Nat Rev Genet, 7:21–33. 2006.
96.
FinkeJH, ZeaAH, StanleyJ, LongoDL, MizoguchiH, TubbsRR, WiltroutRH, O'SheaJJ, KudohS, KleinE. Loss of T-cell receptor zeta chain and p56lck in T-cells infiltrating human renal cell carcinoma. Cancer Res, 53:5613–5616. 1993.
97.
FinkelT, HolbrookNJ. Oxidants, oxidative stress and the biology of ageing. Nature, 408:239–247. 2000.
98.
FlescherE, LedbetterJA, SchievenGL, Vela-RochN, FossumD, DangH, OgawaN, TalalN. Longitudinal exposure of human T lymphocytes to weak oxidative stress suppresses transmembrane and nuclear signal transduction. J Immunol, 153:4880–4889. 1994.
99.
FloresKG, LiJ, SempowskiGD, HaynesBF, HaleLP. Analysis of the human thymic perivascular space during aging. J Clin Invest, 104:1031–1039. 1999.
100.
FortinCF, LarbiA, DupuisG, LesurO, FulopTJr.GM-CSF activates the Jak/STAT pathway to rescue polymorphonuclear neutrophils from spontaneous apoptosis in young but not elderly individuals. Biogerontology, 8:173–187. 2007.
101.
FortinCF, LesurO, FulopTJr.Effects of aging on triggering receptor expressed on myeloid cells (TREM)-1-induced PMN functions. FEBS Lett, 581:1173–1178. 2007.
102.
FortinCF, McDonaldPP, LesurO, FulopTJr.Aging and neutrophils: there is still much to do. Rejuvenation Res, 11:873–882. 2008.
103.
FranceschiC, BonafeM, ValensinS, OlivieriF, DeLM, OttavianiE, DeBG. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci, 908:244–254. 2000.
104.
FranceschiC, CapriM, MontiD, GiuntaS, OlivieriF, SeviniF, PanourgiaMP, InvidiaL, CelaniL, ScurtiM, CeveniniE, CastellaniGC, SalvioliS. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev, 128:92–105. 2007.
105.
FranceschiC, MontiD, BarbieriD, SalvioliS, GrassilliE, CapriM, TroianoL, GuidoM, BonafeM, TropeaF, SalomoniP, BenattiF, BellesiaE, MacchioniS, AnderliniR, SansoniP, MariottiS, WrattenML, TettaC, CossarizzaA. Successful immunosenescence and the remodelling of immune responses with ageing. Nephrol Dial Transplant, 11,Suppl 9:18–25. 1996.
106.
FranceschiC, MontiD, SansoniP, CossarizzaA. The immunology of exceptional individuals: the lesson of centenarians. Immunol Today, 16:12–16. 1995.
107.
FrascaD, BlombergBB. Effects of aging on B cell function. Current Opinion in Immunology, 21:425–430. 2009.
108.
FrascaD, LandinAM, LechnerSC, RyanJG, SchwartzR, RileyRL, BlombergBB. Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells. J Immunol, 180:5283–5290. 2008.
109.
FrenchRA, BroussardSR, MeierWA, MinshallC, ArkinsS, ZacharyJF, DantzerR, KelleyKW. Age-associated loss of bone marrow hematopoietic cells is reversed by GH and accompanies thymic reconstitution. Endocrinology, 143:690–699. 2002.
110.
FriguetB, BulteauAL, ChondrogianniN, ConconiM, PetropoulosI. Protein degradation by the proteasome and its implications in aging. Ann N Y Acad Sci, 908:143–154. 2000.
111.
FulopTJr., ForisG, WorumI, LeoveyA. Age-dependent alterations of Fc gamma receptor-mediated effector functions of human polymorphonuclear leucocytes. Clin Exp Immunol, 61:425–432. 1985.
112.
FulopT, LarbiA, DouziechN, FortinC, GuerardKP, LesurO, KhalilA, DupuisG. Signal transduction and functional changes in neutrophils with aging. Aging Cell, 3:217–226. 2004.
GantierMP, SadlerAJ, WilliamsBR. Fine-tuning of the innate immune response by microRNAs. Immunol Cell Biol, 85:458–462. 2007.
115.
GarinisGA, van der HorstGT, VijgJ, HoeijmakersJH. DNA damage and ageing: new-age ideas for an age-old problem. Nat Cell Biol, 10:1241–1247. 2008.
116.
GeldermanKA, HultqvistM, HolmbergJ, OlofssonP, HolmdahlR. T cell surface redox levels determine T cell reactivity and arthritis susceptibility. Proc Natl Acad Sci U S A, 103:12831–12836. 2006.
117.
GibsonKL, WuYC, BarnettY, DugganO, VaughanR, KondeatisE, NilssonBO, WikbyA, KiplingD, Dunn-WaltersDK. B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell, 8:18–25. 2009.
118.
GidalevitzT, KikisEA, MorimotoRI. A cellular perspective on conformational disease: the role of genetic background and proteostasis networks. Curr Opin Struct Biol, 20:23–32. 2010.
119.
GillespieGM, WillsMR, AppayV, O'CallaghanC, MurphyM, SmithN, SissonsP, Rowland-JonesS, BellJI, MossPA. Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8(+) T lymphocytes in healthy seropositive donors. J Virol, 74:8140–8150. 2000.
120.
Ginn-PeaseME, WhislerRL. Redox signals and NF-kappaB activation in T cells. Free Radic Biol Med, 25:346–361. 1998.
121.
GoldbergGL, ZakrzewskiJL, PeralesMA, van den BrinkMR. Clinical strategies to enhance T cell reconstitution. Semin Immunol, 19:289–296. 2007.
GreenwayA, AzadA, MillsJ, McPheeD. Human immunodeficiency virus type 1 Nef binds directly to Lck and mitogen-activated protein kinase, inhibiting kinase activity. J Virol, 70:6701–6708. 1996.
124.
GressRE, DeeksSG. Reduced thymus activity and infection prematurely age the immune system. J Clin Invest, 119:2884–2887. 2009.
125.
GrillariJ, KatingerH, VoglauerR. Aging and the ubiquitinome: traditional and non-traditional functions of ubiquitin in aging cells and tissues. Exp Gerontol, 41:1067–1079. 2006.
126.
GringhuisSI, LeowA, Papendrecht-Van Der VoortEA, RemansPH, BreedveldFC, VerweijCL. Displacement of linker for activation of T cells from the plasma membrane due to redox balance alterations results in hyporesponsiveness of synovial fluid T lymphocytes in rheumatoid arthritis. J Immunol, 164:2170–2179. 2000.
127.
GringhuisSI, Papendrecht-Van Der VoortEA, LeowA, Nivine LevarhtEW, BreedveldFC, VerweijCL. Effect of redox balance alterations on cellular localization of LAT and downstream T-cell receptor signaling pathways. Mol Cell Biol, 22:400–411. 2002.
128.
GroettrupM, KirkCJ, BaslerM. Proteasomes in immune cells: more than peptide producers?Nat Rev Immunol, 10:73–78. 2010.
HadzicT, LiL, ChengN, WalshSA, SpitzDR, KnudsonCM. The role of low molecular weight thiols in T lymphocyte proliferation and IL-2 secretion. J Immunol, 175:7965–7972. 2005.
132.
HaleJS, BoursalianTE, TurkGL, FinkPJ. Thymic output in aged mice. Proc Natl Acad Sci U S A, 103:8447–8452. 2006.
133.
HanS, YangK, OzenZ, PengW, MarinovaE, KelsoeG, ZhengB. Enhanced differentiation of splenic plasma cells but diminished long-lived high-affinity bone marrow plasma cells in aged mice. J Immunol, 170:1267–1273. 2003.
134.
HarleyCB, FutcherAB, GreiderCW. Telomeres shorten during ageing of human fibroblasts. Nature, 345:458–460. 1990.
135.
HarmanD. Aging: a theory based on free radical and radiation chemistry. J Gerontol, 11:298–300. 1956.
136.
HarmanD. The free radical theory of aging. Antioxid Redox Signal, 5:557–561. 2003.
137.
HarrisonDE, StrongR, SharpZD, NelsonJF, AstleCM, FlurkeyK, NadonNL, WilkinsonJE, FrenkelK, CarterCS, PahorM, JavorsMA, FernandezE, MillerRA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 460:392–395. 2009.
138.
HaxhinastoS, MathisD, BenoistC. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J Exp Med, 205:565–574. 2008.
139.
HayesSA, DiceJF. Roles of molecular chaperones in protein degradation. J Cell Biol, 132:255–258. 1996.
140.
HaynesBF, MarkertML, SempowskiGD, PatelDD, HaleLP. The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection. Annu Rev Immunol, 18:529–560. 2000.
141.
HaynesL, LintonPJ, EatonSM, TonkonogySL, SwainSL. Interleukin 2, but not other common gamma chain-binding cytokines, can reverse the defect in generation of CD4 effector T cells from naive T cells of aged mice. J Exp Med, 190:1013–1024. 1999.
142.
HaynesL, MaueAC. Effects of aging on T cell function. Current Opinion in Immunology, 21:414–417. 2009.
143.
HerreroC, MarquesL, LloberasJ, CeladaA. IFN-gamma-dependent transcription of MHC class II IA is impaired in macrophages from aged mice. J Clin Invest, 107:485–493. 2001.
144.
HewisonM. Vitamin D and innate immunity. Curr Opin Investig Drugs, 9:485–490. 2008.
145.
HodesRJ. Aging and the immune system. Immunol Rev, 160:5–8. 1997.
146.
HoefigKP, HeissmeyerV. MicroRNAs grow up in the immune system. Curr Opin Immunol, 20:281–287. 2008.
147.
HolloszyJO, FontanaL. Caloric restriction in humans. Exp Gerontol, 42:709–712. 2007.
148.
HolloszyJO, SmithEK, ViningM, AdamsS. Effect of voluntary exercise on longevity of rats. J Appl Physiol, 59:826–831. 1985.
HuangMC, LiaoJJ, BonaseraS, LongoDL, GoetzlEJ. Nuclear factor-kappaB-dependent reversal of aging-induced alterations in T cell cytokines. FASEB J, 22:2142–2150. 2008.
151.
HubbsAF, BenkovicSA, MillerDB, O'CallaghanJP, BattelliL, Schwegler-BerryD, MaQ. Vacuolar leukoencephalopathy with widespread astrogliosis in mice lacking transcription factor Nrf2. Am J Pathol, 170:2068–2076. 2007.
152.
HuntKJ, WalshBM, VoegeliD, RobertsHC. Inflammation in aging part 1: physiology and immunological mechanisms. Biol Res Nurs, 11:245–252. 2010.
153.
HuppertFA, SolomouW, O'ConnorS, MorganK, SussamsP, BrayneC. Aging and lymphocyte subpopulations: whole-blood analysis of immune markers in a large population sample of healthy elderly individuals. Exp Gerontol, 33:593–600. 1998.
154.
HusomAD, PetersEA, KollingEA, FugereNA, ThompsonLV, FerringtonDA. Altered proteasome function and subunit composition in aged muscle. Arch Biochem Biophys, 421:67–76. 2004.
155.
HwangJS, HwangJS, ChangI, KimS. Age-associated decrease in proteasome content and activities in human dermal fibroblasts: restoration of normal level of proteasome subunits reduces aging markers in fibroblasts from elderly persons. J Gerontol A Biol Sci Med Sci, 62:490–499. 2007.
156.
HwangKA, KimHR, KangI. Aging and human CD4(+) regulatory T cells. Mech Ageing Dev, 130:509–517. 2009.
157.
ItoK, HiraoA, AraiF, TakuboK, MatsuokaS, MiyamotoK, OhmuraM, NakaK, HosokawaK, IkedaY, SudaT. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med, 12:446–451. 2006.
158.
ItoY, PonnappanU, LipschitzDA. Excess formation of lysophosphatidic acid with age inhibits myristic acid-induced superoxide anion generation in intact human neutrophils. FEBS Lett, 394:149–152. 1996.
159.
JacksonSP, BartekJ. The DNA-damage response in human biology and disease. Nature, 461:1071–1078. 2009.
160.
JamiesonBD, DouekDC, KillianS, HultinLE, Scripture-AdamsDD, GiorgiJV, MarelliD, KoupRA, ZackJA. Generation of functional thymocytes in the human adult. Immunity, 10:569–575. 1999.
161.
Janssen-HeiningerYM, PoynterME, BaeuerlePA. Recent advances towards understanding redox mechanisms in the activation of nuclear factor kappaB. Free Radic Biol Med, 28:1317–1327. 2000.
162.
JenqRR, KingCG, VolkC, SuhD, SmithOM, RaoUK, YimNL, HollandAM, LuSX, ZakrzewskiJL, GoldbergGL, DiabA, AlpdoganO, PenackO, NaIK, KappelLW, WolchokJD, HoughtonAN, PeralesMA, van den BrinkMR. Keratinocyte growth factor enhances DNA plasmid tumor vaccine responses after murine allogeneic bone marrow transplantation. Blood, 113:1574–1580. 2009.
163.
JingY, GravensteinS, ChagantyNR, ChenN, LyerlyKH, JoyceS, DengY. Aging is associated with a rapid decline in frequency, alterations in subset composition, and enhanced Th2 response in CD1d-restricted NKT cells from human peripheral blood. Exp Gerontol, 42:719–732. 2007.
164.
JohnsonJA, JohnsonDA, KraftAD, CalkinsMJ, JakelRJ, VargasMR, ChenPC. The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration. Ann N Y Acad Sci, 1147:61–69. 2008.
165.
JungKJ, LeeEK, KimJY, ZouY, SungB, HeoHS, KimMK, LeeJ, KimND, YuBP, ChungHY. Effect of short term calorie restriction on pro-inflammatory NF-kB and AP-1 in aged rat kidney. Inflamm Res, 58:143–150. 2009.
KashinoG, KodamaS, NakayamaY, SuzukiK, FukaseK, GotoM, WatanabeM. Relief of oxidative stress by ascorbic acid delays cellular senescence of normal human and Werner syndrome fibroblast cells. Free Radic Biol Med, 35:438–443. 2003.
168.
KatoM, SlackFJ. microRNAs: small molecules with big roles—C. elegans to human cancer. Biol Cell, 100:71–81. 2008.
169.
KawaharaTL, MichishitaE, AdlerAS, DamianM, BerberE, LinM, McCordRA, OngaiguiKC, BoxerLD, ChangHY, ChuaKF. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell, 136:62–74. 2009.
170.
KawakamiK, NakamuraA, IshigamiA, GotoS, TakahashiR. Age-related difference of site-specific histone modifications in rat liver. Biogerontology, 10:415–421. 2009.
171.
KhanN, ShariffN, CobboldM, BrutonR, AinsworthJA, SinclairAJ, NayakL, MossPA. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol, 169:1984–1992. 2002.
172.
KhazaeliAA, TatarM, PletcherSD, CurtsingerJW. Heat-induced longevity extension in Drosophila. I. Heat treatment, mortality, and thermotolerance. J Gerontol A Biol Sci Med Sci, 52:B48–B52. 1997.
173.
KiffinR, KaushikS, ZengM, BandyopadhyayU, ZhangC, MasseyAC, Martinez-VicenteM, CuervoAM. Altered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age. J Cell Sci, 120:782–791. 2007.
174.
KimHJ, BarajasB, WangM, NelAE. Nrf2 activation by sulforaphane restores the age-related decrease of T(H)1 immunity: role of dendritic cells. J Allergy Clin Immunol, 121:1255–1261. 2008.
175.
KlineGH, HaydenTA, KlinmanNR. B cell maintenance in aged mice reflects both increased B cell longevity and decreased B cell generation. J Immunol, 162:3342–3349. 1999.
176.
KlionskyDJ. The molecular machinery of autophagy: unanswered questions. J Cell Sci, 118:7–18. 2005.
177.
KohlerS, WagnerU, PiererM, KimmigS, OppmannB, MowesB, JulkeK, RomagnaniC, ThielA. Post-thymic in vivo proliferation of naive CD4+ T cells constrains the TCR repertoire in healthy human adults. Eur J Immunol, 35:1987–1994. 2005.
178.
KojimaM, HosodaH, DateY, NakazatoM, MatsuoH, KangawaK. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature, 402:656–660. 1999.
179.
KongF, ChenCH, CooperMD. Thymic function can be accurately monitored by the level of recent T cell emigrants in the circulation. Immunity, 8:97–104. 1998.
180.
KovacsEJ, PalmerJL, FortinCF, FulopTJr., GoldsteinDR, LintonPJ. Aging and innate immunity in the mouse: impact of intrinsic and extrinsic factors. Trends Immunol, 30:319–324. 2009.
181.
KrishnarajR. Immunosenescence of human NK cells: effects on tumor target recognition, lethal hit and interferon sensitivity. Immunol Lett, 34:79–84. 1992.
182.
KrishnarajR, BhoomaT. Cytokine sensitivity of human NK cells during immunosenescence. 2. IL2-induced interferon gamma secretion. Immunol Lett, 50:59–63. 1996.
183.
KuboC, DayNK, GoodRA. Influence of early or late dietary restriction on life span and immunological parameters in MRL/Mp-lpr/lpr mice. Proc Natl Acad Sci U S A, 81:5831–5835. 1984.
184.
KubotaH. Quality control against misfolded proteins in the cytosol: a network for cell survival. J Biochem, 146:609–616. 2009.
185.
KumarR, AvagyanS, SnoeckHW. A quantitative trait locus on chr.4 regulates thymic involution. J Gerontol A Biol Sci Med Sci, 65:620–625. 2010.
186.
KwakMK, ChoJM, HuangB, ShinS, KenslerTW. Role of increased expression of the proteasome in the protective effects of sulforaphane against hydrogen peroxide-mediated cytotoxicity in murine neuroblastoma cells. Free Radic Biol Med, 43:809–817. 2007.
187.
KwakMK, WakabayashiN, GreenlawJL, YamamotoM, KenslerTW. Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol Cell Biol, 23:8786–8794. 2003.
188.
KwonJ, DevadasS, WilliamsMS. T cell receptor-stimulated generation of hydrogen peroxide inhibits MEK-ERK activation and lck serine phosphorylation. Free Radic Biol Med, 35:406–417. 2003.
189.
LabrieJEIII, SahAP, AllmanDM, CancroMP, GersteinRM. Bone marrow microenvironmental changes underlie reduced RAG-mediated recombination and B cell generation in aged mice. J Exp Med, 200:411–423. 2004.
190.
Lafferty-WhyteK, CairneyCJ, JamiesonNB, OienKA, KeithWN. Pathway analysis of senescence-associated miRNA targets reveals common processes to different senescence induction mechanisms. Biochim Biophys Acta, 1792:341–352. 2009.
191.
LagesCS, SuffiaI, VelillaPA, HuangB, WarshawG, HildemanDA, BelkaidY, ChougnetC. Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation. J Immunol, 181:1835–1848. 2008.
192.
LamarkT, JohansenT. Autophagy: links with the proteasome. Curr Opin Cell Biol, 22:192–198. 2009.
193.
LarbiA, DupuisG, DouziechN, KhalilA, FulopTJr.Low-grade inflammation with aging has consequences for T-lymphocyte signaling. Ann N Y Acad Sci, 1030:125–133. 2004.
194.
LarbiA, FranceschiC, MazzattiD, SolanaR, WikbyA, PawelecG. Aging of the immune system as a prognostic factor for human longevity. Physiology (Bethesda), 23:64–74. 2008.
195.
LarbiA, KempfJ, PawelecG. Oxidative stress modulation and T cell activation. Exp Gerontol, 42:852–858. 2007.
196.
LarbiA, KempfJ, Wistuba-HamprechtK, HaugC, PawelecG. The heat shock proteins in cellular aging: is zinc the missing link?Biogerontology, 7:399–408. 2006.
LeeHK, MarzellaL. Regulation of intracellular protein degradation with special reference to lysosomes: role in cell physiology and pathology. Int Rev Exp Pathol, 35:39–147. 1994.
199.
LeiserSF, MillerRA. Nrf2 signaling: a mechanism for cellular stress resistance in long-lived mice. Mol Cell Biol, 30:871–884. 2010.
200.
LevineB, KlionskyDJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell, 6:463–477. 2004.
201.
LevySM, HerbermanRB, LeeJ, WhitesideT, BeadleM, HeidenL, SimonsA. Persistently low natural killer cell activity, age, and environmental stress as predictors of infectious morbidity. Nat Immun Cell Growth Regul, 10:289–307. 1991.
202.
LiC, CapanE, ZhaoY, ZhaoJ, StolzD, WatkinsSC, JinS, LuB. Autophagy is induced in CD4+ T cells and important for the growth factor-withdrawal cell death. J Immunol, 177:5163–5168. 2006.
203.
LiJ, SteinTD, JohnsonJA. Genetic dissection of systemic autoimmune disease in Nrf2-deficient mice. Physiol Genomics, 18:261–272. 2004.
204.
LiY, WangLX, YangG, HaoF, UrbaWJ, HuHM. Efficient cross-presentation depends on autophagy in tumor cells. Cancer Res, 68:6889–6895. 2008.
205.
LicastroF, CandoreG, LioD, PorcelliniE, Colonna-RomanoG, FranceschiC, CarusoC. Innate immunity and inflammation in ageing: a key for understanding age-related diseases. Immun Ageing, 2:8. 2005.
206.
LigthartGJ, CorberandJX, GeertzenHG, MeindersAE, KnookDL, HijmansW. Necessity of the assessment of health status in human immunogerontological studies: evaluation of the SENIEUR protocol. Mech Ageing Dev, 55:89–105. 1990.
207.
LinJ, EpelE, CheonJ, KroenkeC, SinclairE, BigosM, WolkowitzO, MellonS, BlackburnE. Analyses and comparisons of telomerase activity and telomere length in human T and B cells: insights for epidemiology of telomere maintenance. J Immunol Methods, 352:71–80. 2010.
208.
LintonPJ, HaynesL, TsuiL, ZhangX, SwainS. From naive to effector—alterations with aging. Immunol Rev, 160:9–18. 1997.
209.
LithgowGJ, WhiteTM, MelovS, JohnsonTE. Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc Natl Acad Sci U S A, 92:7540–7544. 1995.
LiuL, WylieRC, AndrewsLG, TollefsbolTO. Aging, cancer and nutrition: the DNA methylation connection. Mech Ageing Dev, 124:989–998. 2003.
212.
LombardDB, ChuaKF, MostoslavskyR, FrancoS, GostissaM, AltFW. DNA repair, genome stability, and aging. Cell, 120:497–512. 2005.
213.
LooneyRJ, FalseyA, CampbellD, TorresA, KolassaJ, BrowerC, McCannR, MenegusM, McCormickK, FramptonM, HallW, AbrahamGN. Role of cytomegalovirus in the T cell changes seen in elderly individuals. Clin Immunol, 90:213–219. 1999.
214.
LopatinaN, HaskellJF, AndrewsLG, PooleJC, SaldanhaS, TollefsbolT. Differential maintenance and de novo methylating activity by three DNA methyltransferases in aging and immortalized fibroblasts. J Cell Biochem, 84:324–334. 2002.
LordJM, PhillipsAC, ArltW. Synergistic effects of ageing and stress on neutrophil function. Handbook of Immunosenescence. FulopT, FranceschiC, HirokawaK, PawelecG. Dordrecht, Netherlands: Springer, 2009; 475–498.
217.
LosM, SchenkH, HexelK, BaeuerlePA, DrogeW, Schulze-OsthoffK. IL-2 gene expression and NF-kappa B activation through CD28 requires reactive oxygen production by 5-lipoxygenase. EMBO J, 14:3731–3740. 1995.
218.
LungTL, Saurwein-TeisslM, ParsonW, SchonitzerD, Grubeck-LoebensteinB. Unimpaired dendritic cells can be derived from monocytes in old age and can mobilize residual function in senescent T cells. Vaccine, 18:1606–1612. 2000.
219.
LynchHE, GoldbergGL, ChidgeyA, Van den BrinkMRM, BoydR, SempowskiGD. Thymic involution and immune reconstitution. Trends Immunol, 30:366–373. 2009.
MantovaniA, SozzaniS, LocatiM, AllavenaP, SicaA. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol, 23:549–555. 2002.
222.
MarianiE, MarianiAR, MeneghettiA, TarozziA, CoccoL, FacchiniA. Age-dependent decreases of NK cell phosphoinositide turnover during spontaneous but not Fc-mediated cytolytic activity. Int Immunol, 10:981–989. 1998.
223.
MarianiE, MeneghettiA, NeriS, RavagliaG, FortiP, CattiniL, FacchiniA. Chemokine production by natural killer cells from nonagenarians. Eur J Immunol, 32:1524–1529. 2002.
MaroneG, PotoS, diML, CondorelliM. Human basophil releasability. I. Age-related changes in basophil releasability. J Allergy Clin Immunol, 77:377–383. 1986.
226.
Martinez-VicenteM, SovakG, CuervoAM. Protein degradation and aging. Exp Gerontol, 40:622–633. 2005.
227.
MassieHR, AielloVR, WilliamsTR. Inhibition of iron absorption prolongs the life span of Drosophila. Mech Ageing Dev, 67:227–237. 1993.
228.
MathurSK, SchwantesEA, JarjourNN, BusseWW. Age-related changes in eosinophil function in human subjects. Chest, 133:412–419. 2008.
229.
MatthiasP, YoshidaM, KhochbinS. HDAC6 a new cellular stress surveillance factor. Cell Cycle, 7:7–10. 2008.
230.
MaueAC, YagerEJ, SwainSL, WoodlandDL, BlackmanMA, HaynesL. T-cell immunosenescence: lessons learned from mouse models of aging. Trends Immunol, 30:301–305. 2009.
231.
Mays-HoopesL, ChaoW, ButcherHC, HuangRC. Decreased methylation of the major mouse long interspersed repeated DNA during aging and in myeloma cells. Dev Genet, 7:65–73. 1986.
232.
McElhaneyJE, EffrosRB. Immunosenescence: what does it mean to health outcomes in older adults?Curr Opin Immunol, 21:418–424. 2009.
233.
MessaoudiI, WarnerJ, FischerM, ParkB, HillB, MattisonJ, LaneMA, RothGS, IngramDK, PickerLJ, DouekDC, MoriM, Nikolich-ZugichJ. Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates. Proc Natl Acad Sci U S A, 103:19448–19453. 2006.
234.
MichieCA, McLeanA, AlcockC, BeverleyPC. Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature, 360:264–265. 1992.
235.
MinD, Panoskaltsis-MortariA, KuroO, HollanderGA, BlazarBR, WeinbergKI. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood, 109:2529–2537. 2007.
236.
MiyajiC, WatanabeH, TomaH, AkisakaM, TomiyamaK, SatoY, AboT. Functional alteration of granulocytes, NK cells, and natural killer T cells in centenarians. Hum Immunol, 61:908–916. 2000.
237.
MiyamotoK, ArakiKY, NakaK, AraiF, TakuboK, YamazakiS, MatsuokaS, MiyamotoT, ItoK, OhmuraM, ChenC, HosokawaK, NakauchiH, NakayamaK, NakayamaKI, HaradaM, MotoyamaN, SudaT, HiraoA. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell, 1:101–112. 2007.
MorganTE, WongAM, FinchCE. Anti-inflammatory mechanisms of dietary restriction in slowing aging processes. Interdiscip Top Gerontol, 35:83–97. 2007.
240.
MorimotoRI. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev, 22:1427–1438. 2008.
241.
MorleyJF, BrignullHR, WeyersJJ, MorimotoRI. The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc Natl Acad Sci U S A, 99:10417–10422. 2002.
242.
MotohashiH, YamamotoM. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med, 10:549–557. 2004.
243.
MuljoSA, AnselKM, KanellopoulouC, LivingstonDM, RaoA, RajewskyK. Aberrant T cell differentiation in the absence of Dicer. J Exp Med, 202:261–269. 2005.
244.
MunzC. Enhancing immunity through autophagy. Annu Rev Immunol, 27:423–449. 2009.
245.
MurataS, TakahamaY, TanakaK. Thymoproteasome: probable role in generating positively selecting peptides. Curr Opin Immunol, 20:192–196. 2008.
246.
MurcianoC, YanezA, O'ConnorJE, GozalboD, GilML. Influence of aging on murine neutrophil and macrophage function against Candida albicans. FEMS Immunol Med Microbiol, 53:214–221. 2008.
247.
NagelJE, ChopraRK, ChrestFJ, McCoyMT, SchneiderEL, HolbrookNJ, AdlerWH. Decreased proliferation, interleukin 2 synthesis, and interleukin 2 receptor expression are accompanied by decreased mRNA expression in phytohemagglutinin-stimulated cells from elderly donors. J Clin Invest, 81:1096–1102. 1988.
248.
NagelJE, PyleRS, ChrestFJ, AdlerWH. Oxidative metabolism and bactericidal capacity of polymorphonuclear leukocytes from normal young and aged adults. J Gerontol, 37:529–534. 1982.
249.
NapolitanoLA, LoJC, GotwayMB, MulliganK, BarbourJD, SchmidtD, GrantRM, HalvorsenRA, SchambelanM, McCuneJM. Increased thymic mass and circulating naive CD4 T cells in HIV-1-infected adults treated with growth hormone. AIDS, 16:1103–1111. 2002.
250.
NardaiG, VeghEM, ProhaszkaZ, CsermelyP. Chaperone-related immune dysfunction: an emergent property of distorted chaperone networks. Trends Immunol, 27:74–79. 2006.
251.
NavonA, CiechanoverA. The 26 S proteasome: from basic mechanisms to drug targeting. J Biol Chem, 284:33713–33718. 2009.
252.
NaylorK, LiG, VallejoAN, LeeWW, KoetzK, BrylE, WitkowskiJ, FulbrightJ, WeyandCM, GoronzyJJ. The influence of age on T cell generation and TCR diversity. J Immunol, 174:7446–7452. 2005.
253.
NguyenT, NioiP, PickettCB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem, 284:13291–13295. 2009.
254.
NguyenT, SherrattPJ, HuangHC, YangCS, PickettCB. Increased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response element. Degradation of Nrf2 by the 26 S proteasome. J Biol Chem, 278:4536–4541. 2003.
255.
NguyenT, SherrattPJ, NioiP, YangCS, PickettCB. Nrf2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1. J Biol Chem, 280:32485–32492. 2005.
256.
NguyenT, SherrattPJ, PickettCB. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol, 43:233–260. 2003.
257.
NiedernhoferLJ, GarinisGA, RaamsA, LalaiAS, RobinsonAR, AppeldoornE, OdijkH, OostendorpR, AhmadA, vanLW, TheilAF, VermeulenW, van der HorstGT, MeineckeP, KleijerWJ, VijgJ, JaspersNG, HoeijmakersJH. A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature, 444:1038–1043. 2006.
258.
NijnikA, WoodbineL, MarchettiC, DawsonS, LambeT, LiuC, RodriguesNP, CrockfordTL, CabuyE, VindigniA, EnverT, BellJI, SlijepcevicP, GoodnowCC, JeggoPA, CornallRJ. DNA repair is limiting for haematopoietic stem cells during ageing. Nature, 447:686–690. 2007.
Nikolich-ZugichJ. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol, 8:512–522. 2008.
261.
Nikolich-ZugichJ, MessaoudiI. Mice and flies and monkeys too: caloric restriction rejuvenates the aging immune system of non-human primates. Exp Gerontol, 40:884–893. 2005.
262.
NishiokaT, ShimizuJ, IidaR, YamazakiS, SakaguchiS. CD4+CD25+Foxp3+ T cells and CD4+CD25-Foxp3+ T cells in aged mice. J Immunol, 176:6586–6593. 2006.
263.
NjeminiR, DemanetC, MetsT. Aging-related differences in basal heat shock protein 70 levels in lymphocytes are linked to altered frequencies of lymphocyte subsets. Aging Cell, 7:498–505. 2008.
264.
NomelliniV, GomezCR, KovacsEJ. Aging and impairment of innate immunity. Contrib Microbiol, 15:188–205. 2008.
265.
O'ConnellRM, TaganovKD, BoldinMP, ChengG, BaltimoreD. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A, 104:1604–1609. 2007.
OgawaK, SuzukiK, OkutsuM, YamazakiK, ShinkaiS. The association of elevated reactive oxygen species levels from neutrophils with low-grade inflammation in the elderly. Immun Ageing, 5:13. 2008.
268.
OikawaS, KawanishiS. Site-specific DNA damage at GGG sequence by oxidative stress may accelerate telomere shortening. FEBS Lett, 453:365–368. 1999.
269.
OsburnWO, YatesMS, DolanPD, ChenS, LibyKT, SpornMB, TaguchiK, YamamotoM, KenslerTW. Genetic or pharmacologic amplification of nrf2 signaling inhibits acute inflammatory liver injury in mice. Toxicol Sci, 104:218–227. 2008.
270.
OspeltC, GayS. TLRs and chronic inflammation. Int J Biochem Cell Biol, 42:495–505. 2010.
271.
OtsujiM, KimuraY, AoeT, OkamotoY, SaitoT. Oxidative stress by tumor-derived macrophages suppresses the expression of CD3 zeta chain of T-cell receptor complex and antigen-specific T-cell responses. Proc Natl Acad Sci U S A, 93:13119–13124. 1996.
272.
OuyangQ, WagnerWM, VoehringerD, WikbyA, KlattT, WalterS, MullerCA, PircherH, PawelecG. Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1)Exp Gerontol, 38:911–920. 2003.
273.
OuyangQ, WagnerWM, WalterS, MullerCA, WikbyA, AubertG, KlattT, StevanovicS, DodiT, PawelecG. An age-related increase in the number of CD8+ T cells carrying receptors for an immunodominant Epstein-Barr virus (EBV) epitope is counteracted by a decreased frequency of their antigen-specific responsiveness. Mech Ageing Dev, 124:477–485. 2003.
274.
PaganelliR, ScalaE, RossoR, CossarizzaA, BertolloL, BarbieriD, FabriziA, LusiEA, FagioloU, FranceschiC. A shift to Th0 cytokine production by CD4+ cells in human longevity: studies on two healthy centenarians. Eur J Immunol, 26:2030–2034. 1996.
275.
PalombellaVJ, ConnerEM, FuselerJW, DestreeA, DavisJM, LarouxFS, WolfRE, HuangJ, BrandS, ElliottPJ, LazarusD, McCormackT, ParentL, SteinR, AdamsJ, GrishamMB. Role of the proteasome and NF-kappaB in streptococcal cell wall-induced polyarthritis. Proc Natl Acad Sci U S A, 95:15671–15676. 1998.
276.
PandaA, ArjonaA, SapeyE, BaiF, FikrigE, MontgomeryRR, LordJM, ShawAC. Human innate immunosenescence: causes and consequences for immunity in old age. Trends Immunol, 30:325–333. 2009.
277.
PangKC, SandersMT, MonacoJJ, DohertyPC, TurnerSJ, ChenW. Immunoproteasome subunit deficiencies impact differentially on two immunodominant influenza virus-specific CD8+ T cell responses. J Immunol, 177:7680–7688. 2006.
PearsonKJ, LewisKN, PriceNL, ChangJW, PerezE, CascajoMV, TamashiroKL, PoosalaS, CsiszarA, UngvariZ, KenslerTW, YamamotoM, EganJM, LongoDL, IngramDK, NavasP, deCR. Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction. Proc Natl Acad Sci U S A, 105:2325–2330. 2008.
281.
PegoraroG, KubbenN, WickertU, GohlerH, HoffmannK, MisteliT. Ageing-related chromatin defects through loss of the NURD complex. Nat Cell Biol, 11:1261–1267. 2009.
282.
PerezVI, BuffensteinR, MasamsettiV, LeonardS, SalmonAB, MeleJ, AndziakB, YangT, EdreyY, FriguetB, WardW, RichardsonA, ChaudhuriA. Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat. Proc Natl Acad Sci U S A, 106:3059–3064. 2009.
PetersenS, SaretzkiG, VonZT. Preferential accumulation of single-stranded regions in telomeres of human fibroblasts. Exp Cell Res, 239:152–160. 1998.
285.
PiatelliMJ, DoughtyC, ChilesTC. Requirement for a hsp90 chaperone-dependent MEK1/2-ERK pathway for B cell antigen receptor-induced cyclin D2 expression in mature B lymphocytes. J Biol Chem, 277:12144–12150. 2002.
286.
PiazzollaG, TortorellaC, SerroneM, JirilloE, AntonaciS. Modulation of cytoskeleton assembly capacity and oxidative response in aged neutrophils. Immunopharmacol Immunotoxicol, 20:251–266. 1998.
287.
PlowdenJ, Renshaw-HoelscherM, EnglemanC, KatzJ, SambharaS. Innate immunity in aging: impact on macrophage function. Aging Cell, 3:161–167. 2004.
288.
PlunkettFJ, FranzeseO, BelaramaniLL, FletcherJM, GilmourKC, SharifiR, KhanN, HislopAD, CaraA, SalmonM, GasparHB, RustinMH, WebsterD, AkbarAN. The impact of telomere erosion on memory CD8+ T cells in patients with X-linked lymphoproliferative syndrome. Mech Ageing Dev, 126:855–865. 2005.
289.
PlunkettFJ, FranzeseO, FinneyHM, FletcherJM, BelaramaniLL, SalmonM, DokalI, WebsterD, LawsonAD, AkbarAN. The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cells is associated with decreased Akt (Ser473) phosphorylation. J Immunol, 178:7710–7719. 2007.
290.
PonnappanU. Ubiquitin-proteasome pathway is compromised in CD45RO+ and CD45RA+ T lymphocyte subsets during aging. Exp Gerontol, 37:359–367. 2002.
291.
PonnappanS, OvaaH, PonnappanU. Lower expression of catalytic and structural subunits of the proteasome contributes to decreased proteolysis in peripheral blood T lymphocytes during aging. Int J Biochem Cell Biol, 39:799–809. 2007.
292.
PonnappanS, PonnappanU. Ubiquitin-proteasome pathway in immune-senescence. Recent Research Developments in Biochemistry Vol. 4 Part II. PandalaiS. Trivandrum, India: Research Signpost, 2003; 779–785.
293.
PonnappanU, TrebilcockGU, ZhengMZ. Studies into the effect of tyrosine phosphatase inhibitor phenylarsine oxide on NFkappaB activation in T lymphocytes during aging: evidence for altered IkappaB-alpha phosphorylation and degradation. Exp Gerontol, 34:95–107. 1999.
294.
PonnappanU, ZhongM, TrebilcockGU. Decreased proteasome-mediated degradation in T cells from the elderly: a role in immune senescence. Cell Immunol, 192:167–174. 1999.
295.
PuaHH, DzhagalovI, ChuckM, MizushimaN, HeYW. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med, 204:25–31. 2007.
296.
PuaHH, HeYW. Maintaining T lymphocyte homeostasis: another duty of autophagy. Autophagy, 3:266–267. 2007.
297.
RabaticS, SabioncelloA, DekarisD, KardumI. Age-related changes in functions of peripheral blood phagocytes. Mech Ageing Dev, 45:223–229. 1988.
298.
RajawatYS, HiliotiZ, BossisI. Aging: central role for autophagy and the lysosomal degradative system. Ageing Res Rev, 8:199–213. 2009.
299.
ReddyNM, KleebergerSR, BreamJH, FallonPG, KenslerTW, YamamotoM, ReddySP. Genetic disruption of the Nrf2 compromises cell-cycle progression by impairing GSH-induced redox signaling. Oncogene, 27:5821–5832. 2008.
300.
ReddyNM, KleebergerSR, ChoHY, YamamotoM, KenslerTW, BiswalS, ReddySP. Deficiency in Nrf2-GSH signaling impairs type II cell growth and enhances sensitivity to oxidants. Am J Respir Cell Mol Biol, 37:3–8. 2007.
301.
ReyesBM, DaneseS, SansM, FiocchiC, LevineAD. Redox equilibrium in mucosal T cells tunes the intestinal TCR signaling threshold. J Immunol, 175:2158–2166. 2005.
302.
RichardsonB. Impact of aging on DNA methylation. Ageing Res Rev, 2:245–261. 2003.
303.
RiderDA, SinclairAJ, YoungSP. Oxidative inactivation of CD45 protein tyrosine phosphatase may contribute to T lymphocyte dysfunction in the elderly. Mech Ageing Dev, 124:191–198. 2003.
304.
RinkL, CakmanI, KirchnerH. Altered cytokine production in the elderly. Mech Ageing Dev, 102:199–209. 1998.
305.
RitzBW, GardnerEM. Malnutrition and energy restriction differentially affect viral immunity. J Nutr, 136:1141–1144. 2006.
306.
RobertMF, MorinS, BeaulieuN, GauthierF, ChuteIC, BarsalouA, MacLeodAR. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Nat Genet, 33:61–65. 2003.
307.
RockKL, GoldbergAL. Degradation of cell proteins and the generation of MHC class I-presented peptides. Annu Rev Immunol, 17:739–779. 1999.
308.
RogersonBJ, HarrisDP, SwainSL, BurgessDO. Germinal center B cells in Peyer's patches of aged mice exhibit a normal activation phenotype and highly mutated IgM genes. Mech Ageing Dev, 124:155–165. 2003.
309.
RomagnoliP, StrahanD, PelosiM, CantagrelA, van MeerwijkJP. A potential role for protein tyrosine kinase p56(lck) in rheumatoid arthritis synovial fluid T lymphocyte hyporesponsiveness. Int Immunol, 13:305–312. 2001.
310.
RossiDJ, BryderD, SeitaJ, NussenzweigA, HoeijmakersJ, WeissmanIL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature, 447:725–729. 2007.
311.
RossiSW, JekerLT, UenoT, KuseS, KellerMP, ZuklysS, GudkovAV, TakahamaY, KrengerW, BlazarBR, HollanderGA. Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood, 109:3803–3811. 2007.
312.
RushmoreTH, MortonMR, PickettCB. The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem, 266:11632–11639. 1991.
313.
SaccaniS, MarazziI, BegAA, NatoliG. Degradation of promoter-bound p65/RelA is essential for the prompt termination of the nuclear factor kappaB response. J Exp Med, 200:107–113. 2004.
314.
SalminenA, KaarnirantaK. Genetics vs. entropy: longevity factors suppress the NF-kappaB-driven entropic aging process. Ageing Res Rev, 9:298–314. 2009.
315.
SalminenA, KaarnirantaK. NF-kappaB signaling in the aging process. J Clin Immunol, 29:397–405. 2009.
316.
SalminenA, KaarnirantaK. Regulation of the aging process by autophagy. Trends Mol Med, 15:217–224. 2009.
317.
SalminenA, KauppinenA, SuuronenT, KaarnirantaK. SIRT1 longevity factor suppresses NF-kappaB -driven immune responses: regulation of aging via NF-kappaB acetylation?Bioessays, 30:939–942. 2008.
318.
SalminenA, OjalaJ, HuuskonenJ, KauppinenA, SuuronenT, KaarnirantaK. Interaction of aging-associated signaling cascades: inhibition of NF-kappaB signaling by longevity factors FoxOs and SIRT1. Cell Mol Life Sci, 65:1049–1058. 2008.
319.
SalminenA, PaimelaT, SuuronenT, KaarnirantaK. Innate immunity meets with cellular stress at the IKK complex: regulation of the IKK complex by HSP70 and HSP90. Immunol Lett, 117:9–15. 2008.
320.
SalomonsFA, Menendez-BenitoV, BottcherC, McCrayBA, TaylorJP, DantumaNP. Selective accumulation of aggregation-prone proteasome substrates in response to proteotoxic stress. Mol Cell Biol, 29:1774–1785. 2009.
321.
SamorajskiT, DelaneyC, DurhamL, OrdyJM, JohnsonJA, DunlapWP. Effect of exercise on longevity, body weight, locomotor performance, and passive-avoidance memory of C57BL/6J mice. Neurobiol Aging, 6:17–24. 1985.
322.
SansoniP, VescoviniR, FagnoniF, BiasiniC, ZanniF, ZanlariL, TeleraA, LucchiniG, PasseriG, MontiD, FranceschiC, PasseriM. The immune system in extreme longevity. Exp Gerontol, 43:61–65. 2008.
323.
SargB, KoutzamaniE, HelligerW, RundquistI, LindnerHH. Postsynthetic trimethylation of histone H4 at lysine 20 in mammalian tissues is associated with aging. J Biol Chem, 277:39195–39201. 2002.
324.
SarkarD, FisherPB. Molecular mechanisms of aging-associated inflammation. Cancer Lett, 236:13–23. 2006.
325.
SauceD, LarsenM, FastenackelsS, DuperrierA, KellerM, Grubeck-LoebensteinB, FerrandC, DebreP, SidiD, AppayV. Evidence of premature immune aging in patients thymectomized during early childhood. J Clin Invest, 119:3070–3078. 2009.
326.
SauerS, BrunoL, HertweckA, FinlayD, LeleuM, SpivakovM, KnightZA, CobbBS, CantrellD, O'ConnorE, ShokatKM, FisherAG, MerkenschlagerM. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A, 105:7797–7802. 2008.
327.
Saurwein-TeisslM, LungTL, MarxF, GschosserC, AschE, BlaskoI, ParsonW, BockG, SchonitzerD, TrannoyE, Grubeck-LoebensteinB. Lack of antibody production following immunization in old age: association with CD8(+)CD28(-) T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines. J Immunol, 168:5893–5899. 2002.
328.
SavinoW. The thymus is a common target organ in infectious diseases. PLoS Pathog, 2:e62. 2006.
329.
SchlisselMS, KafferCR, CurryJD. Leukemia and lymphoma: a cost of doing business for adaptive immunity. Genes Dev, 20:1539–1544. 2006.
330.
SchmidD, PypaertM, MunzC. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity, 26:79–92. 2007.
SchreursMW, HermsenMA, GeltinkRI, ScholtenKB, BrinkAA, KueterEW, TijssenM, MeijerCJ, YlstraB, MeijerGA, HooijbergE. Genomic stability and functional activity may be lost in telomerase-transduced human CD8+ T lymphocytes. Blood, 106:2663–2670. 2005.
333.
SchroderAK, RinkL. Neutrophil immunity of the elderly. Mech Ageing Dev, 124:419–425. 2003.
334.
SchwarzenbachHR, NakagawaT, ConroyMC, de WeckAL. Skin reactivity, basophil degranulation and IgE levels in ageing. Clin Allergy, 12:465–473. 1982.
335.
SebastianC, EspiaM, SerraM, CeladaA, LloberasJ. MacrophAging: a cellular and molecular review. Immunobiology, 210:121–126. 2005.
336.
SedelnikovaOA, HorikawaI, ZimonjicDB, PopescuNC, BonnerWM, BarrettJC. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat Cell Biol, 6:168–170. 2004.
SempowskiGD, GoodingME, LiaoHX, LePT, HaynesBF. T cell receptor excision circle assessment of thymopoiesis in aging mice. Mol Immunol, 38:841–848. 2002.
339.
SempowskiGD, HaleLP, SundyJS, MasseyJM, KoupRA, DouekDC, PatelDD, HaynesBF. Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy. J Immunol, 164:2180–2187. 2000.
340.
SeresI, CsongorJ, MohacsiA, LeoveyA, FulopT. Age-dependent alterations of human recombinant GM-CSF effects on human granulocytes. Mech Ageing Dev, 71:143–154. 1993.
341.
ShengWY, ChenYR, WangTC. A major role of PKC theta and NFkappaB in the regulation of hTERT in human T lymphocytes. FEBS Lett, 580:6819–6824. 2006.
342.
ShodellM, SiegalFP. Circulating, interferon-producing plasmacytoid dendritic cells decline during human ageing. Scand J Immunol, 56:518–521. 2002.
343.
SimonsK, ToomreD. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol, 1:31–39. 2000.
344.
SinclairDA, OberdoerfferP. The ageing epigenome: damaged beyond repair?Ageing Res Rev, 8:189–198. 2009.
345.
SinclairLV, FinlayD, FeijooC, CornishGH, GrayA, AgerA, OkkenhaugK, HagenbeekTJ, SpitsH, CantrellDA. Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat Immunol, 9:513–521. 2008.
346.
SkaugB, JiangX, ChenZJ. The role of ubiquitin in NF-kappaB regulatory pathways. Annu Rev Biochem, 78:769–796. 2009.
347.
SlagboomPE, DroogS, BoomsmaDI. Genetic determination of telomere size in humans: a twin study of three age groups. Am J Hum Genet, 55:876–882. 1994.
348.
SmithRG, JiangH, SunY. Developments in ghrelin biology and potential clinical relevance. Trends Endocrinol Metab, 16:436–442. 2005.
349.
SokolCL, ChuNQ, YuS, NishSA, LauferTM, MedzhitovR. Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat Immunol, 10:713–720. 2009.
350.
SolanaR, PawelecG, TarazonaR. Aging and innate immunity. Immunity, 24:491–494. 2006.
351.
SonNH, JoyceB, HieattA, ChrestFJ, YanovskiJ, WengNP. Stable telomere length and telomerase expression from naive to memory B-lymphocyte differentiation. Mech Ageing Dev, 124:427–432. 2003.
352.
SonNH, MurrayS, YanovskiJ, HodesRJ, WengN. Lineage-specific telomere shortening and unaltered capacity for telomerase expression in human T and B lymphocytes with age. J Immunol, 165:1191–1196. 2000.
353.
SotiC, CsermelyP. Aging and molecular chaperones. Exp Gerontol, 38:1037–1040. 2003.
354.
SouvannavongV, LemaireC, AndreauK, BrownS, AdamA. Age-associated modulation of apoptosis and activation in murine B lymphocytes. Mech Ageing Dev, 103:285–299. 1998.
355.
SpindlerSR. Caloric restriction: from soup to nuts. Ageing Res Rev, 9:324–353. 2010.
356.
StegerMM, MaczekC, Grubeck-LoebensteinB. Morphologically and functionally intact dendritic cells can be derived from the peripheral blood of aged individuals. Clin Exp Immunol, 105:544–550. 1996.
357.
SteinmannGG, KlausB, Muller-HermelinkHK. The involution of the ageing human thymic epithelium is independent of puberty. A morphometric study. Scand J Immunol, 22:563–575. 1985.
358.
StephanRP, SandersVM, WittePL. Stage-specific alterations in murine B lymphopoiesis with age. Int Immunol, 8:509–518. 1996.
359.
StewartD, KilleenE, NaquinR, AlamS, AlamJ. Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium. J Biol Chem, 278:2396–2402. 2003.
360.
StulnigT, MaczekC, BockG, MajdicO, WickG. Reference intervals for human peripheral blood lymphocyte subpopulations from “healthy” young and aged subjects. Int Arch Allergy Immunol, 108:205–210. 1995.
361.
SuhJH, ShenviSV, DixonBM, LiuH, JaiswalAK, LiuRM, HagenTM. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci U S A, 101:3381–3386. 2004.
SwiftME, BurnsAL, GrayKL, DiPietroLA. Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol, 117:1027–1035. 2001.
364.
SykiotisGP, BohmannD. Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila. Dev Cell, 14:76–85. 2008.
365.
TaganovKD, BoldinMP, ChangKJ, BaltimoreD. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A, 103:12481–12486. 2006.
366.
TalMC, SasaiM, LeeHK, YordyB, ShadelGS, IwasakiA. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc Natl Acad Sci U S A, 106:2770–2775. 2009.
367.
TanPH, SagooP, ChanC, YatesJB, CampbellJ, BeutelspacherSC, FoxwellBM, LombardiG, GeorgeAJ. Inhibition of NF-kappa B and oxidative pathways in human dendritic cells by antioxidative vitamins generates regulatory T cells. J Immunol, 174:7633–7644. 2005.
368.
TebbsRS, FlanneryML, MenesesJJ, HartmannA, TuckerJD, ThompsonLH, CleaverJE, PedersenRA. Requirement for the Xrcc1 DNA base excision repair gene during early mouse development. Dev Biol, 208:513–529. 1999.
ThomanML, WeigleWO. Lymphokines and aging: interleukin-2 production and activity in aged animals. J Immunol, 127:2102–2106. 1981.
371.
TomaruU, IshizuA, MurataS, MiyatakeY, SuzukiS, TakahashiS, KazamakiT, OharaJ, BabaT, IwasakiS, FugoK, OtsukaN, TanakaK, KasaharaM. Exclusive expression of proteasome subunit {beta}5t in the human thymic cortex. Blood, 113:5186–5191. 2009.
372.
TonokiA, KuranagaE, TomiokaT, HamazakiJ, MurataS, TanakaK, MiuraM. Genetic evidence linking age-dependent attenuation of the 26S proteasome with the aging process. Mol Cell Biol, 29:1095–1106. 2009.
373.
TortorellaC, SimoneO, PiazzollaG, StellaI, AntonaciS. Age-related impairment of GM-CSF-induced signalling in neutrophils: role of SHP-1 and SOCS proteins. Ageing Res Rev, 6:81–93. 2007.
374.
TothovaZ, KolliparaR, HuntlyBJ, LeeBH, CastrillonDH, CullenDE, McDowellEP, Lazo-KallanianS, WilliamsIR, SearsC, ArmstrongSA, PassegueE, DePinhoRA, GillilandDG. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell, 128:325–339. 2007.
375.
TranQT, XuL, PhanV, GoodwinSB, RahmanM, JinVX, SutterCH, RoebuckBD, KenslerTW, GeorgeEO, SutterTR. Chemical genomics of cancer chemopreventive dithiolethiones. Carcinogenesis, 30:480–486. 2009.
376.
TrebilcockGU, PonnappanU. Evidence for lowered induction of nuclear factor kappa B in activated human T lymphocytes during aging. Gerontology, 42:137–146. 1996.
377.
TsitsiouE, LindsayMA. microRNAs and the immune response. Curr Opin Pharmacol, 9:514–520. 2009.
378.
TsukamotoH, Clise-DwyerK, HustonGE, DusoDK, BuckAL, JohnsonLL, HaynesL, SwainSL. 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, 106:18333–18338. 2009.
379.
TulletJM, HertweckM, AnJH, BakerJ, HwangJY, LiuS, OliveiraRP, BaumeisterR, BlackwellTK. Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell, 132:1025–1038. 2008.
380.
UgarteN, PetropoulosI, FriguetB. Oxidized mitochondrial protein degradation and repair in aging and oxidative stress. Antioxid Redox Signal, 13:539–549. 2010.
381.
VallejoAN. Immune remodeling: lessons from repertoire alterations during chronological aging and in immune-mediated disease. Trends Mol Med, 13:94–102. 2007.
382.
vanDD, MohantyS, ThomasV, GinterS, MontgomeryRR, FikrigE, AlloreHG, MedzhitovR, ShawAC. Age-associated defect in human TLR-1/2 function. J Immunol, 178:970–975. 2007.
383.
vanDD, ShawAC. Toll-like receptors in older adults. J Am Geriatr Soc, 55:1438–1444. 2007.
384.
van den BiggelaarAH, HuizingaTW, de CraenAJ, GusseklooJ, HeijmansBT, FrolichM, WestendorpRG. Impaired innate immunity predicts frailty in old age. The Leiden 85-plus study. Exp Gerontol, 39:1407–1414. 2004.
385.
VellaiT. Autophagy genes and ageing. Cell Death Differ, 16:94–102. 2009.
386.
VenugopalR, JaiswalAK. Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc Natl Acad Sci U S A, 93:14960–14965. 1996.
387.
VerbekeP, ClarkBF, RattanSI. Reduced levels of oxidized and glycoxidized proteins in human fibroblasts exposed to repeated mild heat shock during serial passaging in vitro. Free Radic Biol Med, 31:1593–1602. 2001.
VijgJ. Impact of genome instability on transcription regulation of aging and senescence. Mech Ageing Dev, 125:747–753. 2004.
390.
VittoriniS, ParadisoC, DonatiA, CavalliniG, MasiniM, GoriZ, PolleraM, BergaminiE. The age-related accumulation of protein carbonyl in rat liver correlates with the age-related decline in liver proteolytic activities. J Gerontol A Biol Sci Med Sci, 54:B318–B323. 1999.
391.
WakabayashiN, ItohK, WakabayashiJ, MotohashiH, NodaS, TakahashiS, ImakadoS, KotsujiT, OtsukaF, RoopDR, HaradaT, EngelJD, YamamotoM. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet, 35:238–245. 2003.
392.
WalfordRL, MockD, VerderyR, MacCallumT. Calorie restriction in biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. J Gerontol A Biol Sci Med Sci, 57:B211–B224. 2002.
393.
WanF, LenardoMJ. The nuclear signaling of NF-kappaB: current knowledge, new insights, and future perspectives. Cell Res, 20:24–33. 2010.
394.
WeinbergerB, Herndler-BrandstetterD, SchwanningerA, WeiskopfD, Grubeck-LoebensteinB. Biology of immune responses to vaccines in elderly persons. Clin Infect Dis, 46:1078–1084. 2008.
395.
WeindruchRH, KristieJA, CheneyKE, WalfordRL. Influence of controlled dietary restriction on immunologic function and aging. Fed Proc, 38:2007–2016. 1979.
396.
WeiskopfD, WeinbergerB, Grubeck-LoebensteinB. The aging of the immune system. Transpl Int, 22:1041–1050. 2009.
397.
WengNP. Aging of the immune system: how much can the adaptive immune system adapt?Immunity, 24:495–499. 2006.
398.
WengNP. Telomere and adaptive immunity. Mech Ageing Dev, 129:60–66. 2008.
399.
WengNP, LevineBL, JuneCH, HodesRJ. Regulated expression of telomerase activity in human T lymphocyte development and activation. J Exp Med, 183:2471–2479. 1996.
WhislerRL, ChenM, LiuB, NewhouseYG. Age-related impairments in TCR/CD3 activation of ZAP-70 are associated with reduced tyrosine phosphorylations of zeta-chains and p59fyn/p56lck in human T cells. Mech Ageing Dev, 111:49–66. 1999.
402.
WhislerRL, GrantsIS. Age-related alterations in the activation and expression of phosphotyrosine kinases and protein kinase C (PKC) among human B cells. Mech Ageing Dev, 71:31–46. 1993.
403.
WilliamsMS, KwonJ. T cell receptor stimulation, reactive oxygen species, and cell signaling. Free Radic Biol Med, 37:1144–1151. 2004.
WrightCA, KozikP, ZachariasM, SpringerS. Tapasin and other chaperones: models of the MHC class I loading complex. Biol Chem, 385:763–778. 2004.
406.
WuD, MarkoM, ClaycombeK, PaulsonKE, MeydaniSN. Ceramide-induced and age-associated increase in macrophage COX-2 expression is mediated through up-regulation of NF-kappa B activity. J Biol Chem, 278:10983–10992. 2003.
407.
WuD, MeydaniSN. Age-associated changes in immune and inflammatory responses: impact of vitamin E intervention. J Leukoc Biol, 84:900–914. 2008.
408.
WullschlegerS, LoewithR, HallMN. TOR signaling in growth and metabolism. Cell, 124:471–484. 2006.
409.
XiaoC, RajewskyK. MicroRNA control in the immune system: basic principles. Cell, 136:26–36. 2009.
410.
YanZ, BanerjeeR. Redox remodeling as an immunoregulatory strategy. Biochemistry, 49:1059–1066. 2010.
411.
YanZ, GargSK, KipnisJ, BanerjeeR. Extracellular redox modulation by regulatory T cells. Nat Chem Biol, 5:721–723. 2009.
412.
YangH, YoumYH, DixitVD. Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in age-related thymic involution. J Immunol, 183:3040–3052. 2009.
413.
YeungF, HobergJE, RamseyCS, KellerMD, JonesDR, FryeRA, MayoMW. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J, 23:2369–2380. 2004.
414.
ZeaAH, CurtiBD, LongoDL, AlvordWG, StroblSL, MizoguchiH, CreekmoreSP, O'SheaJJ, PowersGC, UrbaWJ. Alterations in T cell receptor and signal transduction molecules in melanoma patients. Clin Cancer Res, 1:1327–1335. 1995.
415.
ZhangC, CuervoAM. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med, 14:959–965. 2008.
416.
ZhaoY, SunH, LuJ, LiX, ChenX, TaoD, HuangW, HuangB. Lifespan extension and elevated hsp gene expression in Drosophila caused by histone deacetylase inhibitors. J Exp Biol, 208:697–705. 2005.
417.
ZhengH, LiZ. Cutting edge: cross-presentation of cell-associated antigens to MHC class I molecule is regulated by a major transcription factor for heat shock proteins. J Immunol, 173:5929–5933. 2004.
