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The Effect of Age on Thymic Function

Donald B. Palmer

Frontiers in Immunology · 2013 · Review

doi:10.3389/fimmu.2013.00316

Abstract

Age-related regression of the thymus is associated with a decline in naïve T cell output. This is thought to contribute to the reduction in T cell diversity seen in older individuals and linked with increased susceptibility to infection, autoimmune disease, and cancer. Thymic involution is one of the most dramatic and ubiquitous changes seen in the aging immune system, but the mechanisms which underlying this process are poorly understood. However, a picture is emerging, implicating the involvement of both extrinsic and intrinsic factors. In this review we assess the role of the thymic microenvironment as a potential target that regulates thymic involution, question whether thymocyte development in the aged thymus is functionally impaired, and explore the kinetics of thymic involution.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

The Impact of Thymic Involution on Peripheral T Cell Senescence

Advance aging correlates with a reduced ability of the immune system to generate antigen specific responses to pathogens and vaccination. This collectively results in a higher incidence of infection, neoplastic, and autoimmune diseases which are preferentially observed in older individuals. These profound changes exhibited by the aging immune system is termed immunosenescence, which affects both innate and adaptive immunity.

The thymus is responsible for the development of self-restricted, self-tolerant, immunocompetent T cells but has no self-renewal properties relying on the continuous replenishment of new T cell progenitors from the bone marrow. Maturation of these cells occur through a series of proliferation and differentiation stages dependent upon receiving instructions from the specialized thymic microenvironment.

One of the most acknowledged changes of the aging immune system is regression, or involution of the thymus, which seems to occur in almost all vertebrates suggesting that this is an evolutionary ancient and conserved process. Age-associated thymic involution involves a decrease in tissue mass and cellularity, together with a loss of tissue organization with the net outcome being a reduction in naïve T cell output [Figure 1;]. This decline in naïve T cell output is believed to have a major impact on the properties on the peripheral T cell pool such that with increasing age, these cells exhibit alterations in phenotype and function, loss of diversity, and replicative senescence. Moreover, it is these age-related changes in peripheral T cells that are believed to contribute significantly toward the features of immunosenescence, suggesting that the altered thymic activity is a key trigger toward the decline of immune function in the aged.

While animal models show that the maintenance of naïve peripheral T cells in the adult do indeed require the release of cells from the thymus. In humans, however the relationship between thymic activity and naïve T cell homeostasis is a matter of debate, with the recent observations that peripheral proliferation and not thymic output contributes to the maintenance of naïve T cells in young adults. Nevertheless, using signal-joint T cell receptor (TCR) excision circles (sjTREC) as a measurement of thymic function, numerous studies have shown lower sjTREC levels in elderly individuals are associated with a reduction of naïve T cells.

Moreover, a direct correlation between thymic function and naïve T cell number comes from studies examining the peripheral immune system of thymectomized individuals. In one such study which looked at patients 20+ years after thymectomy, the authors observed a decreased proportion of naïve T cells, reduction in TCR diversity and noted that such changes were more marked in individuals infected with Cytomegalovirus. Furthermore, thymectomized individuals exhibited a delayed primary response to tick-borne encephalitis vaccination. Interestingly, these and other studies seem to suggest that the thymus may play a role in maintaining immune efficacy in the adult. Indeed, reports, using mice, have demonstrated the need for the continual production of naïve T cells to mount an effective immune response against bacterial, viral, and fungal infections; with the latter study showing that mice thymectomized at 5 weeks of age exhibited a delayed response to Pneumocystis infection. Furthermore, amongst HIV-infected patients under highly active antiretroviral therapy, those individuals that show enhanced T cell output appear to demonstrate a better prognosis. Furthermore, a recent study proposed that thymic function is a key marker in determining mortality in elderly humans. Thus, the notion that thymus activity may play an important role in host defense of the adult is interesting and clearly merits further investigation.

Changes in Thymocyte Development with Age

Although the exact mechanisms involved in age-associated thymic involution are not fully understood, a picture is emerging suggesting defects are present within both developing thymocytes and thymic stroma. Thymopoiesis involves a series of sequential developmental steps. Briefly, bone marrow progenitors enter into the thymus and are identified by a lack of both CD4 and CD8. Referred to as double negative (DN) thymocytes, these cells differentiate to become double positive (DP), expressing both CD4 and CD8, and subsequently mature into either single positive (SP) CD4 or SP CD8 T cells, through the process of positive and negative selection, and then exit into the periphery.

Given that the thymus requires the continual input of bone marrow progenitors, any age-related alterations in hematopoietic stem cells (HSC) function could conceivably contribute toward thymic involution. Studies have demonstrated that aged HSC appear to exhibit an increased bias toward myeloid differentiation together with a reduced capacity toward lymphoid maturation; which has been observed in mice and human. Such alterations in HSC function may manifest within early thymocyte progenitor (ETP) activity. Indeed, aged mice have fewer numbers of ETP, which exhibit reduced proliferation and differentiation potential. ETP obtained from young mice are able to differentiate into all the stages of T cell development when seeded into fetal thymic organ culture, in contrast aged ETP showed a reduction of T cell differentiation activity. Furthermore, ETP from aged mice show an increased frequency of cells undergoing apoptosis together with a reduced number of Ki67+ cells. ETP are contained within the earliest stages of DN thymocytes and other studies have highlighted further age-related changes within the later stages of DN thymocyte development; with the observation of a decrease in proportion of CD44+CD25+ (DN2) and CD44−CD25+ (DN3) cells. Additionally, a population of CD44+CD24−CD3+ DN cells has been shown to accumulate in the thymus of older mice. Interestingly, a similar population has been identified in adult murine bone marrow which appears to be associated with a role in reducing hematopoiesis, giving rise to the possibility that the accumulation of such cells in the aging thymus might have a negative impact on thymopoiesis thereby contributing to thymic involution.

Further stages in thymocyte maturation also exhibit phenotypical alterations with age; in particular, studies have demonstrated an age-associated decline of CD3 expression on DP and SP thymocytes. Such changes may result in impaired TCR-dependent stimulation. Indeed, it has been demonstrated that aged thymocytes, in comparison to young cells, showed reduced Concanavalin A-induced proliferation, with the observation that aged cells failed to enter into the G2M phase of the cell cycle.

Arguably, these age-related changes in thymopoiesis are likely be acquired by RTE; leading to the possibility that such cells will exhibit reduced immunocompetence. Indeed, several studies have showed that aged RTE undergo phenotypic maturation with delayed kinetics, exhibit decreased proliferative capacity, defective calcium signaling following TCR stimulation, and reduced helper and memory activity. Furthermore, peripheral T cells from older mice exhibit increased resistance to apoptosis which again may be acquired during thymocyte development as it has been demonstrated that thymocytes from older animals are more resistant to apoptosis. It is unlikely that the impairment of aged RTE is acquired in the periphery, but is imprinted during their development in the aged thymus and propose that such flawed cells are also likely to contribute further to peripheral immunosenescence. Moreover, these studies also question, the notion regarding whether T cell development is functionally active in the aged and in light of these studies, this often held view may need to be revised.

Age-Associated Changes in the Thymic Stromal Environment

The thymic stroma plays a crucial role in thymopoiesis by providing the signals necessary to promote proliferation and differentiation due primarily to the influence of cortical and medullary epithelial cells; thus age-related changes in the thymic niches could potentially promote thymic involution. In fact, we have argued that the extrinsic defects within the aged microenvironment contribute significantly to age-associated thymic involution. Several studies have demonstrated that with age, the thymic microenvironment undergoes structural, phenotypical, and architectural changes. This include down regulation of various thymic epithelial cell (TEC) markers such keratin, MHC class II together with alterations of cortical and medullary markers. Furthermore, the structural integrity of the thymic niche is disrupted with age, including disorganization of the cortical and medullary junction; together with increase fibrosis, adipose tissue, and the accumulation of senescent cells in the aged thymus.

The age-associated changes in thymopoiesis would principally imply intrinsic defects, however, closer examination reveal that perhaps such alterations could be due, in part, to extrinsic defects within the aged thymic stromal niche resulting in impaired T cell development. For instance, studies have revealed that the production of IL-7, which is necessary for thymopoiesis, decreases with age. This may be due to the observed loss of MHC class II+ TEC in the aged thymus which has been identified as the cell type responsible for producing IL-7. Moreover, IL-7 administered in older mice and rhesus macaques was shown to increased thymic output. Interestingly, bone marrow from young mice injected into lethally irradiated older mice failed to restore thymic architecture and was still accompanied by a reduction in quantitative thymic function. In an elegant study addressing the repopulation potential of thymic progenitors, Zhu and colleagues transplanted fetal thymic lobes under the kidney capsule of 1-month-old and 18-months-old mice and observed that the total number and proportion of developing thymocytes in the grafts were similar in older and younger host mice. Similar results were obtained when transplanting RAG deficient thymic lobes in that the ability of wild-type thymic progenitors to develop stromal patterning was not dependent on the age of recipients. In contrast, it was observed that intrathymic injection of young ETP fail to develop in older animals but did so in the thymus of young recipients. Furthermore, recent studies revealed that age-associated thymic involution results primarily with changes in gene expression profile in thymic stromal cells.

Above all, these studies suggest that the thymic stroma is a key factor in regulating thymic involution and perhaps the acquired intrinsic defects in aged thymocytes could be due to the inability of the aged thymic microenvironment to support and maintain thymopoiesis. Furthermore, the inter-dependency of both thymocyte and TEC to maintain a functional thymic structure (i.e., thymic cross-talk), is also likely to be a contributing factor toward thymic involution. Indeed, disrupting the integrity of TEC in the adult thymus has been shown to mimic thymic involution. The transcription factor Foxn1, which is essential for TEC development, has been shown to be important for maintaining TEC activity and reducing Foxn1 expression in the postnatal thymus mimics features of thymic involution. In contrast, over expression of Foxn1 delays age-associated thymic involution. Moreover, rejuvenation of the aging thymus has been successful when targeting TEC, with the administration of exogenous keratin growth factor being shown to enhance thymic cellularity, restore thymic architecture, and improve immune function in aged mice. Similar results have also been seen when using growth hormone, sex steroid ablation, ghrelin, and IL-22. However, although such treatment have been effective in directly enhancing thymic activity in the aged, in some instances, this may also be due, in part, by promoting hematopoiesis in the bone marrow.

In addition to the age-related changes observed in TEC, there is an accumulation of adipose tissue particularly in the human thymus and there is increasing evidence indicating that thymic adiposity may inhibit thymic function. In mice, Yang and colleagues demonstrated that inducing obesity in mice accelerated thymic involution. In contrast, in another study, the same group observed that caloric restriction resulted in reduced thymic adiposity and delayed thymic involution. Although it is unclear how increase thymic adiposity alters thymic function, it has been proposed that this is due to the cytokines produced by adipocytes and while involution occurs before fat deposition, suggesting that it is not initiating thymic involution, it may however exacerbate the impact of age on thymic function.

Studies have also noted an increase in the proportion of fibroblasts in the aging thymus of several species including mice, human, and fish; suggesting that this may be a common feature. Several tissues such as heart, kidney, and liver also show increased fibrosis with age which is associated with senescence and impairment of tissue function. Reports have implicated a role for TGFβ and metalloproteinases in the accumulation of fibroblasts in various tissues, which may be activated in response to inflammation as a result of wounding. It is currently unknown whether similar events also occur in the thymus, but may exacerbate the aforementioned alterations seen with age.

Kinetics of Age-Associated Thymic Involution

An often held view is that thymic involution is triggered during puberty. This is based on studies showing that sex steroids have a detrimental effect on thymocytes and that chemical or surgical castration in older rodents is able to restore thymic size. While sex hormones are likely to contribute to thymic regression, the role of these steroids being responsible for initiating thymic involution is now being questioned. Indeed, several studies using a variety of thymic indices (cellularity, epithelial space, number of recent thymic emigrants) have observed that thymic involution occurs early in life, prior to puberty and that the rate of decline is not linear, but appears to be phasic. In mice, thymic cellularity begins to decrease within the first few weeks after birth and a similar picture is evident in human, equine, and zebrafish thymus.

After this rapid early decline, involution appears to proceed at a steady rate, with studies examining human thymus suggesting a rate of 3% of thymic tissue is lost per year until middle age, followed by a rate of 1% per year; which perhaps may cease in later life with studies showing TREC levels being barely detectable in individuals over the age of 85 years.

Overall, these studies strongly suggest that the kinetics of age-associated thymic involution is not uniform throughout life, but characterized by distinct phases and perhaps controlled by different mechanisms. Indeed, the onset of thymic involution occurs much earlier than most acknowledged features of aging and interestingly, microarray analysis of the aged thymic revealed limited overlap with genes normally associated with aging. Thus, we propose that there are at least two phases in thymic involution: the first occurring in early life which would be referred to as “growth-dependent thymic involution,” as it is associated with this period of physiological growth and development and another termed “age-dependent thymic involution” linked to the age-related changes that are occurring in various body systems.

Concluding Remarks

Age-associated thymic involution represents one of the most recognizable features of the aging immune system and is believed to contribute significantly toward immunosenescence. Although the molecular triggers that instigate involution remain to be fully elucidated, both intrinsic and extrinsic factors are thought to contribute toward this process. Moreover, TEC offers a potential target for rejuvenation and requires further exploration. Given the alterations in thymic development in the aged, the evidence suggests that the RTE from the aging thymus are intrinsically defective and could further exacerbate peripheral immunosenescence. Finally, additional factors that are known to modulate thymic function such as pregnancy, infection, inflammatory status, and early life events; i.e., life history is also likely to have an impact on the rate of thymic involution.

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References 90

  1. 1.

    Aw D Silva AB Palmer DB Immunosenescence: emerging challenges for an ageing population. Immunology (2007 ) 120:435–46

    Not in our library10.1111/j.1365-2567.2007.02555.x

  2. 2.

    Shaw AC Joshi S Greenwood H Panda A Lord JM Aging of the innate immune system. Curr Opin Immunol (2010 ) 22:507–13

    Not in our library10.1016/j.coi.2010.05.003

  3. 3.

    McElhaney JE Zhou X Talbot HK Soethout E Bleackley RC Granville DJ The unmet need in the elderly: how immunosenescence, CMV infection, co-morbidities and frailty are a challenge for the development of more effective influenza vaccines. Vaccine (2012 ) 30:2060–7

    Not in our library10.1016/j.vaccine.2012.01.015

  4. 4.

    Anderson G Jenkinson EJ Lymphostromal interactions in thymic development and function. Nat Rev Immunol (2001 ) 1:31–40

    Not in our library10.1038/35095500

  5. 5.

    Ma D Wei Y Liu F Regulatory mechanisms of thymus and T cell development. Dev Comp Immunol (2013 ) 39:91–102

    Not in our library10.1016/j.dci.2011.12.013

  6. 6.

    George AJ Ritter MA Thymic involution with ageing: obsolescence or good housekeeping? Immunol Today (1996 ) 17:267–72

    Not in our library10.1016/0167-5699(96)80543-3

  7. 7.

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

    Not in our library10.1111/j.0105-2896.2005.00275.x

  8. 8.

    Lynch HE Goldberg GL Chidgey A Van den Brink MR Boyd R Sempowski GD Thymic involution and immune reconstitution. Trends Immunol (2009 ) 30:366–73

    Not in our library10.1016/j.it.2009.04.003

  9. 9.

    Shanley DP Aw D Manley NR Palmer DB An evolutionary perspective on the mechanisms of immunosenescence. Trends Immunol (2009 ) 30:374–81

    Not in our library10.1016/j.it.2009.05.001

  10. 10.

    Hohensinner PJ Goronzy JJ Weyand CM Telomere dysfunction, autoimmunity and aging. Aging Dis (2011 ) 2:524–37

    Not in our library

  11. 11.

    Akbar AN Henson SM Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat Rev Immunol (2011 ) 11:289–95

    Not in our library10.1038/nri2959

  12. 12.

    Haynes L Swain SL Why aging T cells fail: implications for vaccination. Immunity (2006 ) 24:663–6

    Not in our library10.1016/j.immuni.2006.06.003

  13. 13.

    Goronzy JJ Weyand CM Understanding immunosenescence to improve responses to vaccines. Nat Rev Immunol (2013 ) 14:428–36

    Not in our library10.1038/ni.2588

  14. 14.

    Aw D Palmer DB The origin and implication of thymic involution. Aging Dis (2011 ) 2:437–43

    Not in our library

  15. 15.

    Cicin-Sain L Messaoudi I Park B Currier N Planer S Fsicher M Dramatic increase in naive T cell turnover is linked to loss of naive T cells from old primates. Proc Natl Acad Sci U S A (2007 ) 104:19960–5

    Not in our library10.1073/pnas.0705905104

  16. 16.

    Bourgeois C Hao Z Rajewsky K Potocnik AJ Stockinger B Ablation of thymic export causes accelerated decay of naive CD4 T cells in the periphery because of activation by environmental antigen. Proc Natl Acad Sci U S A (2008 ) 105:8691–6

    Not in our library10.1073/pnas.0803732105

  17. 17.

    den Braber I Mugwagwa T Vrisekoop N Westera L Mögling R de Boer AB Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans. Immunity (2012 ) 36:288–97

    Not in our library10.1016/j.immuni.2012.02.006

  18. 18.

    Nasi M Troiano L Lugli E Pinti M Ferraresi R Monterastelli E Thymic output and functionality of the IL-7/IL-7 receptor system in centenarians: implications for the neolymphogenesis at the limit of human life. Aging Cell (2006 ) 5:167–75

    Not in our library10.1111/j.1474-9726.2006.00204.x

  19. 19.

    Mitchell WA Lang PO Aspinall R Tracing thymic output in older individuals. Clin Exp Immunol (2010 ) 161:497–503

    Not in our library10.1111/j.1365-2249.2010.04209.x

  20. 20.

    Ferrando-Martínez S Ruiz-Mateos E Hernández A Gutiérrez E Rodríguez-Méndez MM Ordoñez A Age-related deregulation of naive T cell homeostasis in elderly humans. Age (Dordr) (2011 ) 33:197–207

    Not in our library10.1007/s11357-010-9170-8

  21. 21.

    Sauce D Appay V Altered thymic activity in early life: how does it affect the immune system in young adults? Curr Opin Immunol (2011 ) 23:543–8

    Not in our library10.1016/j.coi.2011.05.001

  22. 22.

    Sauce D Larsen M Fastenackels S Duperrier A Keller M Grubeck-Loebenstein B Evidence of premature immune aging in patients thymectomized during early childhood. J Clin Invest (2009 ) 119:3070–8

    Not in our library10.1172/jci39269

  23. 23.

    Prelog M Wilk C Keller M Karall T Orth D Geiger R Diminished response to tick-borne encephalitis vaccination in thymectomized children. Vaccine (2008 ) 26:595–600

    Not in our library10.1016/j.vaccine.2007.11.074

  24. 24.

    Reiley WW Wittmer ST Ryan LM Eaton SM Haynes L Winslow GM Maintenance of peripheral T cell responses during Mycobacterium tuberculosis infection. J Immunol (2012 ) 189:4451–8

    Not in our library10.4049/jimmunol.1201153

  25. 25.

    Vezys V Masopust D Kemball CC Barber DL O’Mara LA Larsen CP Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection. J Exp Med (2006 ) 203:2263–9

    Not in our library10.1084/jem.20060995

  26. 26.

    Shi X Zhang P Sempowski GD Shellito JE Thymopoietic and bone marrow response to murine Pneumocystis pneumonia. Infect Immun (2011 ) 79:2031–42

    Not in our library10.1128/iai.01213-10

  27. 27.

    Douek DC McFarland RD Keiser PH Gage EA Massey JM Haynes BF Changes in thymic function with age and during the treatment of HIV infection. Nature (1998 ) 396:690–5

    Not in our library10.1038/25374

  28. 28.

    de la Rosa R Leal M Thymic involvement in recovery of immunity among HIV-infected adults on highly active antiretroviral therapy. J Antimicrob Chemother (2003 ) 52:155–8

    Not in our library10.1093/jac/dkg311

  29. 29.

    Ferrando-Martínez S Romero-Sánchez MC Solana R Delgado J de la Rosa R Muñoz-Fernández MA Thymic function failure and C-reactive protein levels are independent predictors of all-cause mortality in healthy elderly humans. Age (Dordr) (2013 ) 35:251–9

    Not in our library10.1007/s11357-011-9341-2

  30. 30.

    Linton PJ Dorshkind K Age-related changes in lymphocyte development and function. Nat Immunol (2004 ) 5:133–9

    Not in our library10.1038/ni1033

  31. 31.

    Beerman I Maloney WJ Weissmann IL Rossi DJ Stem cells and the aging hematopoietic system. Curr Opin Immunol (2010 ) 22:500–6

    Not in our library10.1016/j.coi.2010.06.007

  32. 32.

    Van Zant G Liang Y Concise review: hematopoietic stem cell aging, life span, and transplantation. Stem Cells Transl Med (2012 ) 9:651–7

    Not in our library10.5966/sctm.2012-0033

  33. 33.

    Min H Montecino-Rodriguez E Dorshkind K Reduction in the developmental potential of intrathymic T cell progenitors with age. J Immunol (2004 ) 173:245–50

    Not in our library10.4049/jimmunol.173.1.245

  34. 34.

    Heng TS Goldberg GL Gray DH Sutherland JS Chidgey AP Boyd RL Effects of castration on thymocyte development in two different models of thymic involution. J Immunol (2005 ) 175:2982–93

    Not in our library10.4049/jimmunol.175.5.2982

  35. 35.

    Thoman ML The pattern of T lymphocyte differentiation is altered during thymic involution. Mech Ageing Dev (1995 ) 82:155–70

    Not in our library10.1016/0047-6374(95)01597-s

  36. 36.

    Aspinall R Age-associated thymic atrophy in the mouse is due to a deficiency affecting rearrangement of the TCR during intrathymic T cell development. J Immunol (1997 ) 158:3037–45

    Not in our library

  37. 37.

    Li L Hsu HC Grizzle WE Stockard CR Ho KJ Lott P Cellular mechanism of thymic involution. Scand J Immunol (2003 ) 57:410–42

    Not in our library10.1046/j.1365-3083.2003.01206.x

  38. 38.

    Sutherland JS Goldberg GL Hammett MV Uldrich AP Berzins SP Heng TS Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol (2005 ) 175:2741–53

    Not in our library10.4049/jimmunol.175.4.2741

  39. 39.

    Fowlkes BJ Pardoll DM Molecular and cellular events of T cell development. Adv Immunol (1989 ) 44:207–64

    Not in our library10.1016/s0065-2776(08)60643-4

  40. 40.

    Aw D Silva AB Palmer DB Is thymocyte development functional in the aged? Aging (Albany NY) (2009 ) 1:146–53

    Not in our library10.18632/aging.100027

  41. 41.

    Aw D Silva AB Palmer DB The effect of age on the phenotype and function of developing thymocytes. J Comp Pathol (2010 ) 142(Suppl 1):S45–59

    Not in our library10.1016/j.jcpa.2009.10.004

  42. 42.

    Sykes M Unusual T cell populations in adult murine bone marrow. Prevalence of CD3+CD4-CD8- and alpha beta TCR+NK1.1+ cells. J Immunol (1990 ) 145:3209–15

    Not in our library

  43. 43.

    Lau LL Spain LM Altered aging-related thymic involution in T cell receptor transgenic, MHC-deficient, and CD4-deficient mice. Mech Ageing Dev (2000 ) 114:101–21

    Not in our library10.1016/s0047-6374(00)00091-9

  44. 44.

    Leposavic G Pesic V Kosec D Radojevic K Arsenovic-Ranin N Pilipovic I Age-associated changes in CD90 expression on thymocytes and in TCR-dependent stages of thymocyte maturation in male rats. Exp Gerontol (2006 ) 41:574–89

    Not in our library10.1016/j.exger.2006.03.006

  45. 45.

    Hale JS Boursalian TE Turk GL Fink PJ Thymic output in aged mice. Proc Natl Acad Sci U S A (2006 ) 103:8447–52

    Not in our library10.1073/pnas.0601040103

  46. 46.

    Clise-Dwyer K Huston GE Buck AL Duso DK Swain SL Environmental and intrinsic factors lead to antigen unresponsiveness in CD4(+) recent thymic emigrants from aged mice. J Immunol (2007 ) 178:1321–31

    Not in our library10.4049/jimmunol.178.3.1321

  47. 47.

    Eaton SM Maue AC Swain SL Haynes L Bone marrow precursor cells from aged mice generate CD4 T cells that function well in primary and memory responses. J Immunol (2008 ) 181:4825–31

    Not in our library10.4049/jimmunol.181.7.4825

  48. 48.

    Provinciali M Di Stefano G Stronati S Flow cytometric analysis of CD3/TCR complex, zinc, and glucocorticoid-mediated regulation of apoptosis and cell cycle distribution in thymocytes from old mice. Cytometry (1998 ) 32:1–8

    Not in our library10.1002/(sici)1097-0320(19980501)32:1<1::aid-cyto1>3.3.co;2-n

  49. 49.

    Su D-M Aw D Palmer DB Immunosenescence: a product of the environment? Curr Opin Immunol (2013 ) 25:498–503

    Not in our library10.1016/j.coi.2013.05.018

  50. 50.

    Chinn IK Blackburn CC Manley NR Sempowski GD Changes in primary lymphoid organs with aging. Semin Immunol (2012 ) 24:309–20

    Not in our library10.1016/j.smim.2012.04.005

  51. 51.

    Steinmann GG Klaus B Muller-Hermelink HK The involution of the ageing human thymic epithelium is independent of puberty. A morphometric study. Scand J Immunol (1985 ) 22:563–75

    Not in our library10.1111/j.1365-3083.1985.tb01916.x

  52. 52.

    Bertho JM Demarquay C Moulain N Van Der Meeren A Berrih-Aknin S Gourmelon P Phenotypic and immunohistological analyses of the human adult thymus: evidence for an active thymus during adult life. Cell Immunol (1997 ) 179:30–40

    Not in our library10.1006/cimm.1997.1148

  53. 53.

    Ortman CL Dittmar KA Witte PL Le PT Molecular characterization of the mouse involuted thymus: aberrations in expression of transcription regulators in thymocyte and epithelial compartments. Int Immunol (2002 ) 14:813–22

    Not in our library10.1093/intimm/dxf042

  54. 54.

    Gray DH Seach N Ueno T Milton MK Liston A Lew AM Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood (2006 ) 108:3777–85

    Not in our library10.1182/blood-2006-02-004531

  55. 55.

    Aw D Silva AB Maddick MT von Zglinicki T Palmer DB Architectural changes in the thymus of aging mice. Aging Cell (2008 ) 7:158–67

    Not in our library10.1111/j.1474-9726.2007.00365.x

  56. 56.

    Gui J Zhu X Dohkan J Cheng L Barnes PF Su D-M The aged thymus shows normal recruitment of lymphohematopoietic progenitors but has defects in thymic epithelial cells. Int Immunol (2007 ) 19:1201–11

    Not in our library10.1093/intimm/dxm095

  57. 57.

    Dixit VD Thymic fatness and approaches to enhance thymopoietic fitness in aging. Curr Opin Immunol (2010 ) 22:521–8

    Not in our library10.1016/j.coi.2010.06.010

  58. 58.

    Hong C Luckey MA Park JH Intrathymic IL-7: the where, when, and why of IL-7 signaling during T cell development. Semin Immunol (2012 ) 24:151–8

    Not in our library10.1016/j.smim.2012.02.002

  59. 59.

    Aspinall R Andrew D Thymic atrophy in the mouse is a soluble problem of the thymic environment. Vaccine (2000 ) 18:1629–37

    Not in our library10.1016/s0264-410x(99)00498-3

  60. 60.

    Pido-Lopez J Imami N Andrew D Aspinall R Molecular quantitation of thymic output in mice and the effect of IL-7. Eur J Immunol (2002 ) 32:2827–36

    Not in our library10.1002/1521-4141(2002010)32:10<2827::aid-immu2827>3.0.co;2-x

  61. 61.

    Aspinall R Pido-Lopez J Imami N Henson SM Ngom PT Morre M Old rhesus macaques treated with interleukin-7 show increased TREC levels and respond well to influenza vaccination. Rejuvenation Res (2007 ) 10:5–17

    Not in our library10.1089/rej.2006.9098

  62. 62.

    Mackall CL Punt JA Morgan P Farr AG Gress RE Thymic function in young/old chimeras: substantial thymic T cell regenerative capacity despite irreversible age-associated thymic involution. Eur J Immunol (1998 ) 28:1886–93

    Not in our library10.1002/(sici)1521-4141(199806)28:06<1886::aid-immu1886>3.0.co;2-m

  63. 63.

    Zhu X Gui J Dohkan J Cheng L Barnes PF Su D-M Lymphohematopoietic progenitors do not have a synchronized defect with age-related thymic involution. Aging Cell (2007 ) 6:663–72

    Not in our library10.1111/j.1474-9726.2007.00325.x

  64. 64.

    Griffith AV Fallahi M Venables T Petrie HT Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth. Aging Cell (2012 ) 11:169–77

    Not in our library10.1111/j.1474-9726.2011.00773.x

  65. 65.

    Palmer DB Viney JL Ritter MA Hayday AC Owen MJ Expression of the alpha beta T-cell receptor is necessary for the generation of the thymic medulla. Dev Immunol (1993 ) 3:175–9

    Not in our library10.1155/1993/56290

  66. 66.

    Nehls M Pfeifer D Schorpp M Hedrich H Boehm T New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature (1994 ) 1994(372):103–7

    Not in our library10.1038/372103a0

  67. 67.

    Chen L Xiao S Manley NR Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood (2009 ) 113:567–74

    Not in our library10.1182/blood-2008-05-156265

  68. 68.

    Cheng L Guo J Sun L Fu J Barnes PF Metzger D Postnatal tissue-specific disruption of transcription factor FoxN1 triggers acute thymic atrophy. J Biol Chem (2010 ) 285:5836–47

    Not in our library10.1074/jbc.m109.072124

  69. 69.

    Zook EC Krishack PA Zhang S Zeleznik-Le NJ Firulli AB Witte PL Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells. Blood (2011 ) 118:5723–31

    Not in our library10.1182/blood-2011-03-342097

  70. 70.

    Min D Panoskaltsis-Mortari A Kuro OM Hollander GA Blazar BR Weinberg KI Sustained thymopoiesis and improvement in functional immunity induced by exogenous KFG administration in murine models of aging. Blood (2007 ) 109:2529–37

    Not in our library10.1182/blood-2006-08-043794

  71. 71.

    French RA Broussard SR Meier WA Minshall C Arkins S Zachary JF Age-associated loss of bone marrow hematopoietic cells is reversed by GH and accompanies thymic reconstitution. Endocrinology (2002 ) 143:690–9

    Not in our library10.1210/en.143.2.690

  72. 72.

    Olsen NJ Olson G Viselli SM Gu X Kovacs WJ Androgen receptors in thymic epithelium modulate thymus size and thymocyte development. Endocrinology (2001 ) 142:1278–83

    Not in our library10.1210/en.142.3.1278

  73. 73.

    Dixit VD Yang H Sun Y Weeraratna AT Youm YH Smith RG Ghrelin promotes thymopoiesis during aging. J Clin Invest (2007 ) 117:2778–90

    Not in our library10.1172/jci30248

  74. 74.

    Dudakov JA Hanash AM Jenq RR Young LF Ghosh A Singer NV Interleukin-22 drives endogenous thymic regeneration in mice. Science (2012 ) 336:91–5

    Not in our library10.1126/science.1218004

  75. 75.

    Dudakov JA Goldberg GL Reiseger JJ Vlahos K Chidgey AP Boyd RL Sex steroid ablation enhances hematopoietic recovery following cytotoxic antineoplastic therapy in aged mice. J Immunol (2009 ) 183:7084–94

    Not in our library10.4049/jimmunol.0900196

  76. 76.

    Yang H Youm YH Vandanmagsar B Rood J Kumar KG Butler AA Obesity accelerates thymic aging. Blood (2009 ) 114:3803–12

    Not in our library10.1182/blood-2009-03-213595

  77. 77.

    Yang H Youm YH Dixit VD Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in age-related thymic involution. J Immunol (2009 ) 183:3040–52

    Not in our library10.4049/jimmunol.0900562

  78. 78.

    Torroba M Zapata AG Aging of the vertebrate immune system. Microsc Res Tech (2003 ) 62:477–81

    Not in our library10.1002/jemt.10409

  79. 79.

    Khan AS Sane DC Wannenburg T Sonntag WE Growth hormone, insulin-like growth factor-1 and the aging cardiovascular system. Cardiovasc Res (2002 ) 54:25–35

    Not in our library10.1016/s0008-6363(01)00533-8

  80. 80.

    Zhang X Chen X Hong Q Lin H Zhu H Liu Q TIMP-1 promotes age-related renal fibrosis through upregulating ICAM-1 in human TIMP-1 transgenic mice. J Gerontol A Biol Sci Med Sci (2006 ) 61:1130–43

    Not in our library10.1093/gerona/61.11.1130

  81. 81.

    Paradis V Youssef N Dargere D Ba N Bonvoust F Deschatrette J Replicative senescence in normal liver, chronic hepatitis C, and hepatocellular carcinomas. Hum Pathol (2001 ) 32:327–32

    Not in our library10.1053/hupa.2001.22747

  82. 82.

    Gauldie J Kolb M Ask K Martin G Bonniaud P Warburton D Smad3 signaling involved in pulmonary fibrosis and emphysema. Proc Am Thorac Soc (2006 ) 3:696–702

    Not in our library10.1513/pats.200605-125sf

  83. 83.

    Mori R Shaw TJ Martin P Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. J Exp Med (2008 ) 205:43–51

    Not in our library10.1084/jem.20071412

  84. 84.

    Montecino-Rodriquez E Min H Dorshkind K Reevaluating current models of thymic involution. Semin Immunol (2005 ) 17:356–61

    Not in our library10.1016/j.smim.2005.05.006

  85. 85.

    Aw D Palmer DB It’s not all equal: a multiphasic theory of thymic involution. Biogerontology (2012 ) 13:77–81

    Not in our library10.1007/s10522-011-9349-0

  86. 86.

    Jamieson BD Douek DC Killian S Hultin LE Scripture-Adams DD Giorgi JV Generation of functional thymocytes in the human adult. Immunity (1999 ) 10:569–75

    Not in our library10.1016/s1074-7613(00)80056-4

  87. 87.

    Contreiras EC Lenz IHL Meirelles MN Caputo LF Calado TJ Villa-Verde DM The equine thymus microenvironment: a morphological and immunohistochemical analysis. Dev Comp Immunol (2004 ) 28:251–64

    Not in our library10.1016/s0145-305x(03)00134-4

  88. 88.

    Lam SH Chua HL Gong Z Wen Z Lam TJ Sin YM Morphologic transformation of the thymus in developing zebrafish. Dev Dyn (2002 ) 225:87–94

    Not in our library10.1002/dvdy.10127

  89. 89.

    Steinmann GG Changes in the human thymus during aging. Curr Top Pathol (1986 ) 75:43–88

    Not in our library10.1007/978-3-642-82480-7_2

  90. 90.

    Dooley J Liston A Molecular control over thymic involution: from cytokines and microRNA to aging and adipose tissue. Eur J Immunol (2012 ) 42:1073–9

    Not in our library10.1002/eji.201142305

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