Skip to main content

Advertisement

SpringerLink
Log in

Improving immunity in the elderly: current and future lessons from nonhuman primate models

  • Published:
AGE Aims and scope Submit manuscript

Abstract

The immune system must overcome daily challenges from pathogens to protect the body from infection. The success of the immune response to infection relies on the ability to sense and evaluate microbial threats and organize their elimination, while limiting damage to host tissues. This delicate balance is achieved through coordinated action of the innate and adaptive arms of the immune system. Aging results in several structural and functional changes in the immune system, often described under the umbrella term “immune senescence”. Age-related changes affect both the innate and adaptive arms of the immune system and are believed to result in increased susceptibility and severity of infectious diseases, which is further exacerbated by reduced vaccine efficacy in the elderly. Therefore, multiple strategies to improve immune function in the aged are being investigated. Traditionally, studies on immune senescence are conducted using inbred specific pathogen free (SPF) rodents. This animal model has provided invaluable insight into the mechanisms of aging. However, the limited genetic heterogeneity and the SPF status of this model restrict the successful transfer of immunological discoveries between murine models and the clinical setting. More recently, nonhuman primates (NHPs) have emerged as a leading translational model to investigate immune senescence and to test interventions aimed at delaying/reversing age-related changes in immune function. In this article, we review and summarize advances in immuno-restorative approaches investigated in the NHP model system and discuss where the NHP model can support the development of novel therapeutics.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abboud SL, Bethel CR, Aron DC (1991) Secretion of insulin like growth factor I and insulin like growth factor-binding proteins by murine bone marrow stromal cells. J Clin Invest 88:470–475

    Article  PubMed  CAS  Google Scholar 

  • Alpdogan O, van den Brink MR (2005) IL-7 and IL-15: therapeutic cytokines for immunodeficiency. Trends Immunol 26:56–64

    Article  PubMed  CAS  Google Scholar 

  • Alpdogan O, Muriglan SJ, Kappel BJ, Doubrovina E, Schmaltz C, Schiro R, Eng JM, Greenberg AS, Willis LM, Rotolo JA, O'Reilly RJ, van den Brink MR (2003) Insulin-like growth factor-I enhances lymphoid and myeloid reconstitution after allogeneic bone marrow transplantation. Transplantation 75:1977–1983

    Article  PubMed  CAS  Google Scholar 

  • Alpdogan O, Hubbard VM, Smith OM, Patel N, Lu S, Goldberg GL, Gray DH, Feinman J, Kochman AA, Eng JM, Suh D, Muriglan SJ, Boyd RL, van den Brink MR (2006) Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration. Blood 107:2453–2460

    Article  PubMed  CAS  Google Scholar 

  • Andersson AK, Feldmann M, Brennan FM (2008) Neutralizing IL-21 and IL-15 inhibits pro-inflammatory cytokine production in rheumatoid arthritis. Scand J Immunol 68:103–111

    Article  PubMed  CAS  Google Scholar 

  • Appt SE, Clarkson TB, Hoyer PB, Kock ND, Goode AK, May MC, Persyn JT, Vail NK, Ethun KF, Chen H, Sen N, Kaplan JR (2010) Experimental induction of reduced ovarian reserve in a nonhuman primate model (Macaca fascicularis). Comp Med 60:380–388

    PubMed  CAS  Google Scholar 

  • Aspinall R, Del Giudice G, Effros RB, Grubeck-Loebenstein B, Sambhara S (2007) Challenges for vaccination in the elderly. Immun Ageing 4:9

    Article  PubMed  CAS  Google Scholar 

  • Behringer RR, Lewin TM, Quaife CJ, Palmiter RD, Brinster RL, D'Ercole AJ (1990) Expression of insulin-like growth factor I stimulates normal somatic growth in growth hormone-deficient transgenic mice. Endocrinology 127:1033–1040

    Article  PubMed  CAS  Google Scholar 

  • Beq S, Nugeyre M-T, Fang RHT, Gautier D, Legrand R, Schmitt N, Estaquier J, Barre-Sinoussi F, Hurtrel B, Cheynier R, Israel N (2006) IL-7 induces immunological improvement in SIV-infected rhesus macaques under antiviral therapy. J Immunol 176:914–922

    PubMed  CAS  Google Scholar 

  • Boyman O, Purton JF, Surh CD, Sprent J (2007) Cytokines and T-cell homeostasis. Current Opinion in Immunology 19:320–326

    Article  PubMed  CAS  Google Scholar 

  • Butts CL, Shukair SA, Duncan KM, Bowers E, Horn C, Belyavskaya E, Tonelli L, Sternberg EM (2007) Progesterone inhibits mature rat dendritic cells in a receptor-mediated fashion. Int Immunol 19:287–296

    Article  PubMed  CAS  Google Scholar 

  • Cefalu WT, Wagner JD, Bell-Farrow AD, Edwards IJ, Terry JG, Weindruch R, Kemnitz JW (1999) Influence of caloric restriction on the development of atherosclerosis in nonhuman primates: progress to date. Toxicol Sci 52:49–55

    PubMed  CAS  Google Scholar 

  • Chapman IM, Bach MA, Van Cauter E, Farmer M, Krupa D, Taylor AM, Schilling LM, Cole KY, Skiles EH, Pezzoli SS, Hartman ML, Veldhuis JD, Gormley GJ, Thorner MO (1996) Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects. J Clin Endocrinol Metab 81:4249–4257

    Article  PubMed  CAS  Google Scholar 

  • Chu YW, Schmitz S, Choudhury B, Telford W, Kapoor V, Garfield S, Howe D, Gress RE (2008) Exogenous insulin-like growth factor 1 enhances thymopoiesis predominantly through thymic epithelial cell expansion. Blood 112:2836–2846

    Article  PubMed  CAS  Google Scholar 

  • Cicin-Sain L, Messaoudi I, Park B, Currier N, Planer S, Fischer M, Tackitt S, Nikolich-Zugich D, Legasse A, Axthelm MK, Picker LJ, Mori M, Nikolich-Zugich J (2007) Dramatic increase in naive T cell turnover is linked to loss of naive T cells from old primates. Proc Natl Acad Sci USA 104:19960–19965

    Article  PubMed  CAS  Google Scholar 

  • Cicin-Sain L, Smyk-Pearson S, Currier N, Byrd L, Koudelka C, Robinson T, Swarbrick G, Tackitt S, Legasse A, Fischer M, Nikolich-Zugich D, Park B, Hobbs T, Doane CJ, Mori M, Axthelm MK, Lewinsohn DA, Nikolich-Zugich J (2010) Loss of naive T cells and repertoire constriction predict poor response to vaccination in old primates. J Immunol 184:6739–6745

    Article  PubMed  CAS  Google Scholar 

  • Colao A, Amato G, Pedroncelli AM, Baldelli R, Grottoli S, Gasco V, Petretta M, Carella C, Pagani G, Tambura G, Lombardi G (2002a) Gender- and age-related differences in the endocrine parameters of acromegaly. J Endocrinol Invest 25:532–538

    PubMed  CAS  Google Scholar 

  • Colao A, Ferone D, Marzullo P, Panza N, Pivonello R, Orio F Jr, Grande G, Bevilacqua N, Lombardi G (2002b) Lymphocyte subset pattern in acromegaly. J Endocrinol Invest 25:125–128

    PubMed  CAS  Google Scholar 

  • Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ, Ouslander JG, Weyand CM, Goronzy JJ (2008) T cell subset-specific susceptibility to aging. Clin Immunol 27(1):107–118

    Article  CAS  Google Scholar 

  • Danilenko DM, Ring BD, Yanagihara D, Benson W, Wiemann B, Starnes CO, Pierce GF (1995) Keratinocyte growth factor is an important endogenous mediator of hair follicle growth, development, and differentiation. Normalization of the nu/nu follicular differentiation defect and amelioration of chemotherapy-induced alopecia. Am J Pathol 147:145–154

    PubMed  CAS  Google Scholar 

  • De Martinis M, Franceschi C, Monti D, Ginaldi L (2005) Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett 579:2035–2039

    Article  PubMed  CAS  Google Scholar 

  • de Mello Coelho V, Villa-Verde DM, Farias-de-Oliveira DA, de Brito JM, Dardenne M, Savino W (2002) Functional insulin-like growth factor-1/insulin-like growth factor-1 receptor-mediated circuit in human and murine thymic epithelial cells. Neuroendocrinology 75:139–150

    Article  PubMed  Google Scholar 

  • de Mello-Coelho V, Gagnerault MC, Souberbielle JC, Strasburger CJ, Savino W, Dardenne M, Postel-Vinay MC (1998) Growth hormone and its receptor are expressed in human thymic cells. Endocrinology 139:3837–3842

    Article  PubMed  Google Scholar 

  • Deguchi K, Kamada M, Irahara M, Maegawa M, Yamamoto S, Ohmoto Y, Murata K, Yasui T, Yamano S, Aono T (2001) Postmenopausal changes in production of type 1 and type 2 cytokines and the effects of hormone replacement therapy. Menopause 8:266–273

    Article  PubMed  CAS  Google Scholar 

  • Delpy L, Douin-Echinard V, Garidou L, Bruand C, Saoudi A, Guery JC (2005) Estrogen enhances susceptibility to experimental autoimmune myasthenia gravis by promoting type 1-polarized immune responses. J Immunol 175:5050–5057

    PubMed  CAS  Google Scholar 

  • Dixit VD, Schaffer EM, Pyle RS, Collins GD, Sakthivel SK, Palaniappan R, Lillard JW Jr, Taub DD (2004) Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest 114:57–66

    PubMed  CAS  Google Scholar 

  • Dixit VD, Yang H, Sun Y, Weeraratna AT, Youm YH, Smith RG, Taub DD (2007) Ghrelin promotes thymopoiesis during aging. J Clin Invest 117:2778–2790

    Article  PubMed  CAS  Google Scholar 

  • Douek DC, Koup RA (2000) Evidence for thymic function in the elderly. Vaccine 18:1638–1641

    Article  PubMed  CAS  Google Scholar 

  • Effros RB (2005) Roy Walford and the immunologic theory of aging. Immun Ageing 2:7

    Article  PubMed  Google Scholar 

  • Engelmann F, Barron A, Urbanski H, Neuringer M, Kohama SG, Park B, Messaoudi I (2010) Accelerated immune senescence and reduced response to vaccination in ovariectomized female rhesus macaques. Age (Dordr) 33(3):275–289

    Article  CAS  Google Scholar 

  • Ershler WB, Coe CL, Gravenstein S, Schultz KT, Klopp RG (1988a) Specific antibody synthesis in vitro. IV. The correlation of in vitro and in vivo antibody response to influenza vaccine in rhesus monkeys. Clin Exp Immunol 73:355–359

    PubMed  CAS  Google Scholar 

  • Ershler WB, Coe CL, Laughlin N, Klopp RG, Gravenstein S, Roecker EB, Schultz KT (1988b) Aging and immunity in non-human primates. II. Lymphocyte response in thymosin treated middle-aged monkeys. J Gerontol 43:B142–B146

    PubMed  CAS  Google Scholar 

  • Ershler WB, Gravenstein S, Geloo ZS (2007) Thymosin alpha 1 as an adjunct to influenza vaccination in the elderly: rationale and trial summaries. Ann N Y Acad Sci 1112:375–384

    Article  PubMed  CAS  Google Scholar 

  • Evans MJ, MacLaughlin S, Marvin RD, Abdou NI (1997) Estrogen decreases in vitro apoptosis of peripheral blood mononuclear cells from women with normal menstrual cycles and decreases TNF-alpha production in SLE but not in normal cultures. Clin Immunol Immunopathol 82:258–262

    Article  PubMed  CAS  Google Scholar 

  • Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, Casti A, Franceschi C, Passeri M, Sansoni P (2000) Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging. Blood 95:2860–2868

    PubMed  CAS  Google Scholar 

  • Fry TJ, Moniuszko M, Creekmore S, Donohue SJ, Douek DC, Giardina S, Hecht TT, Hill BJ, Komschlies K, Tomaszewski J, Franchini G, Mackall CL (2003) IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates. Blood 101:2294–2299

    Article  PubMed  CAS  Google Scholar 

  • Gagnerault MC, Postel-Vinay MC, Dardenne M (1996) Expression of growth hormone receptors in murine lymphoid cells analyzed by flow cytofluorometry. Endocrinology 137:1719–1726

    Article  PubMed  CAS  Google Scholar 

  • Giglio T, Imro MA, Filaci G, Scudeletti M, Puppo F, De Cecco L, Indiveri F, Costantini S (1994) Immune cell circulating subsets are affected by gonadal function. Life Sci 54:1305–1312

    Article  PubMed  CAS  Google Scholar 

  • Goodwin K, Viboud C, Simonsen L (2006) Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 24:1159–1169

    Article  PubMed  CAS  Google Scholar 

  • Grossmann A, Rabinovitch PS, Lane MA, Jinneman JC, Ingram DK, Wolf NS, Cutler RG, Roth GS (1995) Influence of age, sex, and dietary restriction on intracellular free calcium responses of CD4+ lymphocytes in rhesus monkeys (Macaca mulatta). J Cell Physiol 162:298–303

    Article  PubMed  CAS  Google Scholar 

  • Hansen BR, Kolte L, Haugaard SB, Dirksen C, Jensen FK, Ryder LP, Sorensen AL, Flyvbjerg A, Nielsen SD, Andersen O (2009) Improved thymic index, density and output in HIV-infected patients following low-dose growth hormone therapy: a placebo controlled study. AIDS 23:2123–2131

    Article  PubMed  CAS  Google Scholar 

  • High KP (2004) Infection as a cause of age-related morbidity and mortality. Ageing Res Rev 3:1–14

    Article  PubMed  Google Scholar 

  • Hughes GC, Thomas S, Li C, Kaja M-K, Clark EA (2008) Cutting edge: progesterone regulates IFN-alpha production by plasmacytoid dendritic cells. J Immunol 180:2029–2033

    PubMed  CAS  Google Scholar 

  • Jankovic V, Messaoudi I, Nikolich-Zugich J (2003) Phenotypic and functional T-cell aging in rhesus macaques (Macaca mulatta): differential behavior of CD4 and CD8 subsets. Blood 102:3244–3251

    Article  PubMed  CAS  Google Scholar 

  • Kabelitz D, Medzhitov R (2007) Innate immunity—cross-talk with adaptive immunity through pattern recognition receptors and cytokines. Curr Opin Immunol 19:1–3

    Article  PubMed  CAS  Google Scholar 

  • Kelijman M (1991) Age-related alterations of the growth hormone/insulin-like-growth-factor I axis. J Am Geriatr Soc 39:295–307

    PubMed  CAS  Google Scholar 

  • Kim M-J, Aiken JM, Havighurst T, Hollander J, Ripple MO, Weindruch R (1997) Adult-onset energy restriction of rhesus monkeys attenuates oxidative stress-induced cytokine expression by peripheral blood mononuclear cells. J Nutr 127:2293–2301

    PubMed  CAS  Google Scholar 

  • Klein SL, Jedlicka A, Pekosz A (2010) The Xs and Y of immune responses to viral vaccines. Lancet Infect Dis 10(5):338–349

    Article  PubMed  CAS  Google Scholar 

  • Knyszynski A, Adler-Kunin S, Globerson A (1992) Effects of growth hormone on thymocyte development from progenitor cells in the bone marrow. Brain Behav Immun 6:327–340

    Article  PubMed  CAS  Google Scholar 

  • Koo GC, Huang C, Camacho R, Trainor C, Blake JT, Sirotina-Meisher A, Schleim KD, Wu TJ, Cheng K, Nargund R, McKissick G (2001) Immune enhancing effect of a growth hormone secretagogue. J Immunol 166:4195–4201

    PubMed  CAS  Google Scholar 

  • Kooijman R, Lauf JJ, Kappers AC, Rijkers GT (1995a) Insulin-like growth factor induces phosphorylation of immunoreactive insulin receptor substrate and its association with phosphatidylinositol-3 kinase in human thymocytes. J Exp Med 182:593–597

    Article  PubMed  CAS  Google Scholar 

  • Kooijman R, Scholtens LE, Rijkers GT, Zegers BJ (1995b) Type I insulin-like growth factor receptor expression in different developmental stages of human thymocytes. J Endocrinol 147:203–209

    Article  PubMed  CAS  Google Scholar 

  • Koyama S, Ishii KJ, Coban C, Akira S (2008) Innate immune response to viral infection. Cytokine 43:336–341

    Article  PubMed  CAS  Google Scholar 

  • Kozlowski PA, Williams SB, Lynch RM, Flanigan TP, Patterson RR, Cu-Uvin S, Neutra MR (2002) Differential induction of mucosal and systemic antibody responses in women after nasal, rectal, or vaginal immunization: influence of the menstrual cycle. J Immunol 169:566–574

    PubMed  CAS  Google Scholar 

  • Kumru S, Godekmerdan A, Yilmaz B (2004) Immune effects of surgical menopause and estrogen replacement therapy in peri-menopausal women. J Reprod Immunol 63:31–38

    Article  PubMed  CAS  Google Scholar 

  • Lane MA, Ingram DK, Cutler RG, Knapka JJ, Barnard DE, Roth GS (1992) Dietary restriction in nonhuman primates: progress report on the NIA study. Ann N Y Acad Sci 673:36–45

    Article  PubMed  CAS  Google Scholar 

  • Lane MA, Reznick AZ, Tilmont EM, Lanir A, Ball SS, Read V, Ingram DK, Cutler RG, Roth GS (1995) Aging and food restriction alter some indices of bone metabolism in male rhesus monkeys (Macaca mulatta). J Nutr 125:1600–1610

    PubMed  CAS  Google Scholar 

  • Lane MA, Ingram DK, Roth GS (1999) Calorie restriction in nonhuman primates: effects on diabetes and cardiovascular disease risk. Toxicol Sci 52:41–48

    PubMed  CAS  Google Scholar 

  • Leng J, Goldstein DR (2010) Impact of aging on viral infections. Microbes and Infection 12:1120–1124

    Article  PubMed  Google Scholar 

  • Leone A, Picker LJ, Sodora DL (2009) IL-2, IL-7 and IL-15 as immuno-modulators during SIV/HIV vaccination and treatment. Curr HIV Res 7:83–90

    Article  PubMed  CAS  Google Scholar 

  • LeRoith D, Yanowski J, Kaldjian EP, Jaffe ES, LeRoith T, Purdue K, Cooper BD, Pyle R, Adler W (1996) The effects of growth hormone and insulin-like growth factor I on the immune system of aged female monkeys. Endocrinology 137:1071–1079

    Article  PubMed  CAS  Google Scholar 

  • Litman GW, Rast JP, Fugmann SD (2010) The origins of vertebrate adaptive immunity. Nat Rev Immunol 10:543–553

    Article  PubMed  CAS  Google Scholar 

  • Liu JL, LeRoith D (1999) Insulin-like growth factor I is essential for postnatal growth in response to growth hormone. Endocrinology 140:5178–5184

    Article  PubMed  CAS  Google Scholar 

  • Mascarucci P, Taub D, Saccani S, Paloma MA, Dawson H, Roth GS, Ingram DK, Lane MA (2001) Age-related changes in cytokine production by leukocytes in rhesus monkeys. Aging (Milano) 13:85–94

    CAS  Google Scholar 

  • Mascarucci P, Taub D, Saccani S, Paloma MA, Dawson H, Roth GS, Lane MA, Ingram DK (2002) Cytokine responses in young and old rhesus monkeys: effect of caloric restriction. J Interferon Cytokine Res 22:565–571

    Article  PubMed  CAS  Google Scholar 

  • Masoro EJ (2009) Caloric restriction-induced life extension of rats and mice: a critique of proposed mechanisms. Biochim Biophys Acta 1790:1040–1048

    Article  PubMed  CAS  Google Scholar 

  • McCay CM (1933) Is longevity compatible with optimum growth? Science 77:410–411

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Messaoudi I, Warner J, Fischer M, Park B, Hill B, Mattison J, Lane MA, Roth GS, Ingram DK, Picker LJ, Douek DC, Mori M, Nikolich-Zugich J (2006) Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates. Proc Natl Acad Sci USA 103:19448–19453

    Article  PubMed  CAS  Google Scholar 

  • Messaoudi I, Fischer M, Warner J, Park B, Mattison J, Ingram DK, Totonchy T, Mori M, Nikolich-Zugich J (2008) Optimal window of caloric restriction onset limits its beneficial impact on T-cell senescence in primates. Aging Cell 7:908–919

    Article  PubMed  CAS  Google Scholar 

  • Min D, Taylor PA, Panoskaltsis-Mortari A, Chung B, Danilenko DM, Farrell C, Lacey DL, Blazar BR, Weinberg KI (2002) Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation. Blood 99:4592–4600

    Article  PubMed  CAS  Google Scholar 

  • Min D, Panoskaltsis-Mortari A, Kuro OM, Hollander GA, Blazar BR, Weinberg KI (2007) Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 109:2529–2537

    Article  PubMed  CAS  Google Scholar 

  • Mondal MS, Date Y, Yamaguchi H, Toshinai K, Tsuruta T, Kangawa K, Nakazato M (2005) Identification of ghrelin and its receptor in neurons of the rat arcuate nucleus. Regul Pept 126:55–59

    Article  PubMed  CAS  Google Scholar 

  • Moniuszko M, Fry T, Tsai W-P, Morre M, Assouline B, Cortez P, Lewis MG, Cairns S, Mackall C, Franchini G (2004) Recombinant interleukin-7 induces proliferation of naive macaque CD4+ and CD8+ T cells in vivo. J Virol 78:9740–9749

    Article  PubMed  CAS  Google Scholar 

  • Montecino-Rodriguez E, Clark R, Dorshkind K (1998) Effects of insulin-like growth factor administration and bone marrow transplantation on thymopoiesis in aged mice. Endocrinology 139:4120–4126

    Article  PubMed  CAS  Google Scholar 

  • Napolitano LA, Lo JC, Gotway MB, Mulligan K, Barbour JD, Schmidt D, Grant RM, Halvorsen RA, Schambelan M, McCune JM (2002) Increased thymic mass and circulating naive CD4 T cells in HIV-1-infected adults treated with growth hormone. AIDS 16:1103–1111

    Article  PubMed  CAS  Google Scholar 

  • Napolitano LA, Schmidt D, Gotway MB, Ameli N, Filbert EL, Ng MM, Clor JL, Epling L, Sinclair E, Baum PD, Li K, Killian ML, Bacchetti P, McCune JM (2008) Growth hormone enhances thymic function in HIV-1-infected adults. J Clin Invest 118:1085–1098

    PubMed  CAS  Google Scholar 

  • Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, Witkowski J, Fulbright J, Weyand CM, Goronzy JJ (2005) The influence of age on T cell generation and TCR diversity. J Immunol 174:7446–7452

    PubMed  CAS  Google Scholar 

  • Nightingale SL (1995) From the Food and Drug Administration. JAMA 273:982

    Article  PubMed  CAS  Google Scholar 

  • Nikolich-Zugich J (2005) T cell aging: naive but not young. J Exp Med 201:837–840

    Article  PubMed  CAS  Google Scholar 

  • Nikolich-Zugich J (2007) Non-human primate models of T-cell reconstitution. Semin Immunol 19:310–317

    Article  PubMed  CAS  Google Scholar 

  • Nugeyre MT, Monceaux V, Beq S, Cumont MC, Ho Tsong Fang R, Chene L, Morre M, Barre-Sinoussi F, Hurtrel B, Israel N (2003) IL-7 stimulates T cell renewal without increasing viral replication in simian immunodeficiency virus-infected macaques. J Immunol 171:4447–4453

    PubMed  CAS  Google Scholar 

  • Osborne TB, Mendel LB, Ferry EL (1917) The effect of retardation of growth upon the breeding period and duration of life of rats. Science 45:294–295

    Article  PubMed  CAS  Google Scholar 

  • Pawelec G, Larbi A, Derhovanessian E (2010) Senescence of the human immune system. J Comp Pathol 142(Suppl 1):S39–S44

    Article  PubMed  CAS  Google Scholar 

  • Picker LJ, Reed-Inderbitzin EF, Hagen SI, Edgar JB, Hansen SG, Legasse A, Planer S, Piatak M Jr, Lifson JD, Maino VC, Axthelm MK, Villinger F (2006) IL-15 induces CD4 effector memory T cell production and tissue emigration in nonhuman primates. J Clin Invest 116:1514–1524

    Article  PubMed  CAS  Google Scholar 

  • Pires A, Pido-Lopez J, Moyle G, Gazzard B, Gotch F, Imami N (2004) Enhanced T-cell maturation, differentiation and function in HIV-1-infected individuals after growth hormone and highly active antiretroviral therapy. Antivir Ther 9:67–75

    PubMed  CAS  Google Scholar 

  • Porter VR, Greendale GA, Schocken M, Zhu X, Effros RB (2001) Immune effects of hormone replacement therapy in post-menopausal women. Exp Gerontol 36:311–326

    Article  PubMed  CAS  Google Scholar 

  • Posnett DN, Sinha R, Kabak S, Russo C (1994) Clonal populations of T cells in normal elderly humans: the T cell equivalent to "benign monoclonal gammapathy". J Exp Med 179:609–618

    Article  PubMed  CAS  Google Scholar 

  • Purton JF, Tan JT, Rubinstein MP, Kim DM, Sprent J, Surh CD (2007) Antiviral CD4+ memory T cells are IL-15 dependent. J Exp Med 204:951–961

    Article  PubMed  CAS  Google Scholar 

  • Ramsey JJ, Colman RJ, Binkley NC, Christensen JD, Gresl TA, Kemnitz JW, Weindruch R (2000) Dietary restriction and aging in rhesus monkeys: the University of Wisconsin study. Exp Gerontol 35:1131–1149

    Article  PubMed  CAS  Google Scholar 

  • Rider V, Jones S, Evans M, Bassiri H, Afsar Z, Abdou NI (2001) Estrogen increases CD40 ligand expression in T cells from women with systemic lupus erythematosus. J Rheumatol 28:2644–2649

    PubMed  CAS  Google Scholar 

  • Roberts SB, Schoeller DA (2007) Human caloric restriction for retardation of aging: current approaches and preliminary data. J Nutr 137:1076–1077

    PubMed  CAS  Google Scholar 

  • Roecker EB, Kemnitz JW, Ershler WB, Weindruch R (1996) Reduced immune responses in rhesus monkeys subjected to dietary restriction. J Gerontol A Biol Sci Med Sci 51:B276–B279

    Article  PubMed  CAS  Google Scholar 

  • Rudman D (1985) Growth hormone, body composition, and aging. J Am Geriatr Soc 33:800–807

    PubMed  CAS  Google Scholar 

  • Saucedo R, Rico G, Basurto L, Ochoa R, Zarate A (2002) Transdermal estradiol in menopausal women depresses interleukin-6 without affecting other markers of immune response. Gynecol Obstet Invest 53:114–117

    Article  PubMed  CAS  Google Scholar 

  • Saurwein-Teissl M, Lung TL, Marx F, Gschosser C, Asch E, Blasko I, Parson W, Bock G, Schonitzer D, Trannoy E, Grubeck-Loebenstein B (2002) 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

    PubMed  CAS  Google Scholar 

  • Schluns KS, Kieper WC, Jameson SC, Lefrancois L (2000) Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat Immunol 1:426–432

    Article  PubMed  CAS  Google Scholar 

  • Schwab R, Szabo P, Manavalan JS, Weksler ME, Posnett DN, Pannetier C, Kourilsky P, Even J (1997) Expanded CD4+ and CD8+ T cell clones in elderly humans. J Immunol 158:4493–4499

    PubMed  CAS  Google Scholar 

  • Seggewiss R, Einsele H (2007) Hematopoietic growth factors including keratinocyte growth factor in allogeneic and autologous stem cell transplantation. Semin Hematol 44:203–211

    Article  PubMed  CAS  Google Scholar 

  • Seggewiss R, Lore K, Guenaga FJ, Pittaluga S, Mattapallil J, Chow CK, Koup RA, Camphausen K, Nason MC, Meier-Schellersheim M, Donahue RE, Blazar BR, Dunbar CE, Douek DC (2007) Keratinocyte growth factor augments immune reconstitution after autologous hematopoietic progenitor cell transplantation in rhesus macaques. Blood 110:441–449

    Article  PubMed  CAS  Google Scholar 

  • Sirohi B, Powles R, Morgan G, Treleaven J, Kulkarni S, Horton C, Saso R, Rolfe D, Cook G, Shaw C, Wass J (2007) Use of physiological doses of human growth hormone in haematological patients receiving intensive chemotherapy promotes haematopoietic recovery: a double-blind randomized, placebo-controlled study. Bone Marrow Transplant 39:115–120

    Article  PubMed  CAS  Google Scholar 

  • Smaniotto S, de Mello-Coelho V, Villa-Verde DM, Pleau JM, Postel-Vinay MC, Dardenne M, Savino W (2005) Growth hormone modulates thymocyte development in vivo through a combined action of laminin and CXC chemokine ligand 12. Endocrinology 146:3005–3017

    Article  PubMed  CAS  Google Scholar 

  • Sportes C, Hakim FT, Memon SA, Zhang H, Chua KS, Brown MR, Fleisher TA, Krumlauf MC, Babb RR, Chow CK, Fry TJ, Engels J, Buffet R, Morre M, Amato RJ, Venzon DJ, Korngold R, Pecora A, Gress RE, Mackall CL (2008) Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med 205:1701–1714

    Article  PubMed  CAS  Google Scholar 

  • Suenaga R, Evans MJ, Mitamura K, Rider V, Abdou NI (1998) Peripheral blood T cells and monocytes and B cell lines derived from patients with lupus express estrogen receptor transcripts similar to those of normal cells. J Rheumatol 25:1305–1312

    PubMed  CAS  Google Scholar 

  • Surh CD, Sprent J (2008) Homeostasis of naive and memory T cells. Immunity 29:848–862

    Article  PubMed  CAS  Google Scholar 

  • Tan JT, Dudl E, LeRoy E, Murray R, Sprent J, Weinberg KI, Surh CD (2001) IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc Natl Acad Sci USA 98:8732–8737

    Article  PubMed  CAS  Google Scholar 

  • Taylor LD, Daniels CK, Schmucker DL (1992) Ageing compromises gastrointestinal mucosal immune response in the rhesus monkey. Immunology 75:614–618

    PubMed  CAS  Google Scholar 

  • Vallejo AN (2005) CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev 205:158–169

    Article  PubMed  CAS  Google Scholar 

  • Verland S, Gammeltoft S (1989) Functional receptors for insulin-like growth factors I and II in rat thymocytes and mouse thymoma cells. Mol Cell Endocrinol 67:207–216

    Article  PubMed  CAS  Google Scholar 

  • Verthelyi D (2001) Sex hormones as immunomodulators in health and disease. Int Immunopharmacol 1:983–993

    Article  PubMed  CAS  Google Scholar 

  • Verthelyi DI, Ahmed SA (1998) Estrogen increases the number of plasma cells and enhances their autoantibody production in nonautoimmune C57BL/6 mice. Cell Immunol 189:125–134

    Article  PubMed  CAS  Google Scholar 

  • Vural P, Akgul C, Canbaz M (2006a) Effects of hormone replacement therapy on plasma pro-inflammatory and anti-inflammatory cytokines and some bone turnover markers in postmenopausal women. Pharmacol Res 54:298–302

    Article  PubMed  CAS  Google Scholar 

  • Vural P, Canbaz M, Akgul C (2006b) Effects of menopause and postmenopausal tibolone treatment on plasma TNFalpha, IL-4, IL-10, IL-12 cytokine pattern and some bone turnover markers. Pharmacol Res 53:367–371

    Article  PubMed  CAS  Google Scholar 

  • Walford RL (1969) The immunologic theory of aging. Munksgaard, Copenhagen

    Google Scholar 

  • Weigent DA, Blalock JE (1991) The production of growth hormone by subpopulations of rat mononuclear leukocytes. Cell Immunol 135:55–65

    Article  PubMed  CAS  Google Scholar 

  • Weinberger B, Herndler-Brandstetter D, Schwanninger A, Weiskopf D, Grubeck-Loebenstein B (2008) Vaccines: biology of immune responses to vaccines in elderly persons. Clin Infect Dis 46:1078–1084

    Article  PubMed  Google Scholar 

  • Weindruch R, Gottesman SR, Walford RL (1982) Modification of age-related immune decline in mice dietarily restricted from or after midadulthood. Proc Natl Acad Sci USA 79:898–902

    Article  PubMed  CAS  Google Scholar 

  • Weindruch R, Lane MA, Ingram DK, Ershler WB, Roth GS (1997) Dietary restriction in rhesus monkeys: lymphopenia and reduced mitogen-induced proliferation in peripheral blood mononuclear cells. Aging (Milano) 9:304–308

    CAS  Google Scholar 

  • Whitacre CC, Reingold SC, O'Looney PA (1999) A gender gap in autoimmunity. Science 283:1277–1278

    Article  PubMed  CAS  Google Scholar 

  • Willcox BJ, Willcox DC, Todoriki H, Fujiyoshi A, Yano K, He Q, Curb JD, Suzuki M (2007) Caloric restriction, the traditional Okinawan diet, and healthy aging: the diet of the world's longest-lived people and its potential impact on morbidity and life span. Ann NY Acad Sci 1114:434–455

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by NCRR core grant RR00163, NIH AG 037042, and American Heart Association grant 0930234N. Ilhem Messaoudi and Kristen Haberthur are supported by a fellowship from the Brookdale Foundation.

Author information

Authors and Affiliations

  1. Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, USA

    Christine Meyer, Amelia Kerns, Kristen Haberthur & Ilhem Messaoudi

  2. Graduate Program in Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA

    Kristen Haberthur & Ilhem Messaoudi

  3. Division of Pathobiology and Immunology, Oregon National Primate Research Center, Beaverton, OR, USA

    Ilhem Messaoudi

  4. Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR, 97006, USA

    Ilhem Messaoudi

Authors
  1. Christine Meyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amelia Kerns
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kristen Haberthur
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ilhem Messaoudi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ilhem Messaoudi.

About this article

Cite this article

Meyer, C., Kerns, A., Haberthur, K. et al. Improving immunity in the elderly: current and future lessons from nonhuman primate models. AGE 34, 1157–1168 (2012). https://doi.org/10.1007/s11357-011-9353-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-011-9353-y

Keywords

Search

Navigation