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Thymic involution
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<h2 id="progression">Progression</h2> <h3>Neonatal period</h3> <p>Though the thymus is fully developed before birth,<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> newborns have an essentially empty peripheral immune compartment immediately after birth.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a><a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> Hence, T lymphocytes are not present in the peripheral <a href="/facts/Lymphatic_system/yw5QLgMT">lymphoid tissues</a>, where naïve, mature lymphocytes are stimulated to respond to pathogens.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> In order to populate the peripheral system, the thymus increases in size and upregulates its function during the early <a href="/facts/Neonate/gaEL1QL4">neonatal</a> period.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p> <h3>Age-relatedness</h3> <p>Though some sources[<i>which?</i>] continue to cite <a href="/facts/Puberty/vjfPAKf4">puberty</a> as the time of onset, studies have shown thymic involution to start much earlier.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> The crucial distinction came from the observation that the thymus consists of two main components: the true thymic epithelial space (TES) and the perivascular space (PVS).<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> Thymopoiesis, or T-cell maturation, only occurs in the former. In humans, the TES starts decreasing from the first year of life at a rate of 3% until middle age (35–45 years of age), whereupon it decreases at a rate of 1% until death.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> Hypothetically, the thymus should stop functioning at around 105 years of age;<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> but, studies with <a href="/facts/Bone_marrow/4dfudk0H">bone marrow</a> transplant patients have shown that the thymi of the majority of patients over forty were unable to build a naïve T cell compartment.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> </p><p>With both qualitative and quantitative changes to thymus production occurring as age increases, thymic involution corresponds with the progressive deterioration of the stroma of the thymus and a significant loss of thymic epithelial cells (TECs). Thymic epithelial cells aid in Thymopoiesis and the development of new T-cells. <a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p> <h2 id="effects-of-the-involution">Effects of the involution</h2> <p>The ability of the immune system to mount a strong protective response depends on the receptor diversity of <a href="/facts/Naive_T_cell/QEl3A7Yh">naive T cells</a> (TCR). Thymic involution results in a decreased output of naïve T lymphocytes – mature T cells that are tolerant to self <a href="/facts/Antigen/9JlAernG">antigens</a>, responsive to foreign antigens, but have not yet been stimulated by a foreign substance. In adults, naïve T-cells are hypothesized to be primarily maintained through homeostatic proliferation, or cell division of existing naïve T cells. Though homeostatic proliferation helps sustain TCR even with minimal to nearly absent thymic activity, it does not increase the receptor diversity.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> For yet unknown reasons, TCR diversity drops drastically around age 65.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> Loss of thymic function and TCR diversity is thought to contribute to weaker <a href="/facts/Cancer_immunotherapy/0QKPeh5x">immunosurveillance</a> of the elderly, including increasing instances of diseases such as cancers, autoimmunity, and opportunistic infections.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> </p> <h3>Acute thymic involution and treatment implications</h3> <p>There is growing evidence that thymic involution is plastic and can be therapeutically halted or reversed in order to help boost the immune system. Under certain circumstances, the thymus has been shown to undergo acute thymic involution (alternatively called transient involution).<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> For example, transient involution has been induced in humans and other animals by <a href="/facts/Stress_(biology)/H29jPp2B">stresses</a><a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> such as <a href="/facts/Infection/182XrncP">infections</a>,<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a><a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> <a href="/facts/Pregnancy/vEKYGpep">pregnancy</a>,<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> and <a href="/facts/Malnutrition/KasQy5MR">malnutrition</a>.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a><a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a><a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> The thymus has also been shown to decrease during <a href="/facts/Hibernation/oltroTtp">hibernation</a> and, in frogs, change in size depending on the season, growing smaller in the winter.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> Studies on acute thymic <a href="/facts/Involution_(medicine)/KD5lsdrm">involution</a> may help in developing <a href="/facts/Immunotransplant/kB3XDEbc">treatments</a> for patients, who for example are unable to restore immune function after <a href="/facts/Chemotherapy/fWTLbaUT">chemotherapy</a>, <a href="/facts/Ionizing_radiation/vw0d9GaT">ionizing radiation</a>, or infections like <a href="/facts/HIV/ulY2rgzu">HIV</a>.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> Research has shown the rate of thymus <a href="/facts/Involution_(medicine)/KD5lsdrm">involution</a> to reduce when, for men the <a href="/facts/Testes/Doy40hoq">testes</a>, or for women the <a href="/facts/Ovaries/z2hG6bNy">ovaries</a>, were removed; demonstrating that <a href="/facts/Sex_hormones/mI6bkHII">sex hormones</a>, and especially <a href="/facts/Testosterone/uUumdhAz">testosterone</a>, have a marked influence on the <a href="/facts/Involution_(medicine)/KD5lsdrm">involution</a> process. However, the manner in which the <a href="/facts/Sex_hormones/mI6bkHII">sex hormones</a> moderate this process is not yet fully understood. In other research the results of the <a href="/facts/Greg_Fahy/B72LbWd2">Greg Fahy</a> TRIIM trial showed clinically significant reversal of thymus <a href="/facts/Involution_(medicine)/KD5lsdrm">involution</a> after the administration of <a href="/facts/Human_growth_hormone/SLEJ1fws">human growth hormone</a> (HGH), <a href="/facts/Dehydroepiandrosterone/djLk75uF">Dehydroepiandrosterone</a> (DHEA) and <a href="/facts/Metformin/ScXHFaPT">metformin</a>.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> The two results could mean that HGH and mTOR inhibition in autophagy reverses thymus involution with testosterone advancing thymus involution.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> </p> <h2 id="unknown-selective-pressures">Unknown selective pressures</h2> <p>Thymic involution remains an evolutionary mystery since it occurs in most vertebrates despite its negative effects. </p><p>Since it is not induced by senescence, many scientists have hypothesized that there may have been evolutionary pressures for the organ to involute. A few hypotheses are as follows: </p> <ul><li>Developing T cells that interact strongly with antigen being presented within the thymus are induced to undergo programmed cell death. The intended effect is deletion of self-reactive T cells. This works well when the antigen being presented within the thymus is truly of self origin, but antigen from pathogenic microbes that happens to infiltrate the thymus has the potential to subvert the entire process. Rather than deleting T cells that would cause autoimmunity, T cells capable of eliminating the infiltrating pathogen are deleted instead. It has been proposed that one way to minimize this problem is to produce as many long-lived T cells as possible during the time of life when the thymus is most likely to be pristine, which generally would be when organisms are very young and under the protection of a functional maternal immune system.<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> Thus, in mice and humans, for example, the best time to have a prodigiously functional thymus is prior to birth.</li></ul> In turn, it is well known from <a href="/facts/George_Christopher_Williams/6QWSaCzt">Williams</a>'<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> theory of the evolution of senescence that strong selection for enhanced early function readily accommodates, through <a href="/facts/Antagonistic_pleiotropy_hypothesis/a0FK2dcD"><i>antagonistic pleiotropy</i></a>, deleterious later occurring effects, thus potentially accounting for the especially early demise of the thymus. <ul><li>The <a href="/facts/Disposable_soma_theory_of_aging/nWDckwfs"><i>disposable soma hypothesis</i></a> and <i>life history hypothesis</i> say similarly that tradeoffs are involved in thymic involution. Since the immune system must compete with other bodily systems, notably reproduction, for limited physiological resources, the body must invest in the immune system differentially at different stages of life. There is high immunological investment in youth since immunological memory is low.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a></li> <li>There are also hypotheses that suggest that thymic involution is <i>directly</i> adaptive. For example, some hypotheses have proposed that thymic involution may help in avoidance of autoimmunity or other dangers,<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> prevention of infection,<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> and production of an optimal repertoire of T-cells.<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a></li> <li><i><a href="/facts/Zinc_deficiency/bfrcrw24">Zinc deficiency</a></i> may also play a role.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a></li></ul> <h2 id="external-links">External links</h2> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Shanley D.P.; Danielle A.W.; Manley N.R.; Palmer D.B.; et al. (2009). "An evolutionary perspective on the mechanisms of immunosenescence" (PDF). Trends in Immunology. 30 (7): 374–381. doi:10.1016/j.it.2009.05.001. PMID 19541538. <a href="https://rvc-repository.worktribe.com/preview/1642595/Equine%20Veterinary%20Journal%20-%202023%20-%20Knowles.pdf" target="_blank">https://rvc-repository.worktribe.com/preview/1642595/Equine%20Veterinary%20Journal%20-%202023%20-%20Knowles.pdf</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Shanley D.P.; Danielle A.W.; Manley N.R.; Palmer D.B.; et al. (2009). "An evolutionary perspective on the mechanisms of immunosenescence" (PDF). Trends in Immunology. 30 (7): 374–381. doi:10.1016/j.it.2009.05.001. PMID 19541538. <a href="https://rvc-repository.worktribe.com/preview/1642595/Equine%20Veterinary%20Journal%20-%202023%20-%20Knowles.pdf" target="_blank">https://rvc-repository.worktribe.com/preview/1642595/Equine%20Veterinary%20Journal%20-%202023%20-%20Knowles.pdf</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Zakharova L.A. (2009). "Evolution of adaptive immunity". Izvestiia Rossiĭskoĭ Akademii Nauk. Seriia Biologicheskaia. 2 (2): 143–154. PMID 19391473. <a href="/wiki/PMID_(identifier)" target="_blank">/wiki/PMID_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Linton P.J.; Dorshkind K. (2004). "Age-related changes in lymphocyte development and function". Nature Immunology. 5 (2): 133–139. doi:10.1038/ni1033. PMID 14749784. S2CID 12485241. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Palmer S.; Albergante L.; Blackburn C.C.; Newman T.J. (2018). "Thymic involution and rising disease incidence with age". Proceedings of the National Academy of Sciences of the United States of America. 115 (8): 1883–1888. Bibcode:2018PNAS..115.1883P. doi:10.1073/pnas.1714478115. PMC 5828591. PMID 29432166. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828591" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828591</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Taub D.D.; Long D.L. (2005). "Insights into thymic aging and regeneration". Immunological Reviews. 205: 72–93. doi:10.1111/j.0105-2896.2005.00275.x. PMID 15882346. S2CID 24461464. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Steinmann G.G.; Klaus B.; Muller-Hermelin H.K.; et al. (1985). "The involution of the aging human thymic epithelium is independent of puberty. A morphometric study". Scandinavian Journal of Immunology. 22 (5): 563–75. doi:10.1111/j.1365-3083.1985.tb01916.x. PMID 4081647. 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Journal of Immunology. 172 (1): 15–19. doi:10.4049/jimmunol.172.1.15. PMID 14688303. <a href="https://doi.org/10.4049%2Fjimmunol.172.1.15" target="_blank">https://doi.org/10.4049%2Fjimmunol.172.1.15</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Shanley D.P.; Danielle A.W.; Manley N.R.; Palmer D.B.; et al. (2009). "An evolutionary perspective on the mechanisms of immunosenescence" (PDF). Trends in Immunology. 30 (7): 374–381. doi:10.1016/j.it.2009.05.001. PMID 19541538. <a href="https://rvc-repository.worktribe.com/preview/1642595/Equine%20Veterinary%20Journal%20-%202023%20-%20Knowles.pdf" target="_blank">https://rvc-repository.worktribe.com/preview/1642595/Equine%20Veterinary%20Journal%20-%202023%20-%20Knowles.pdf</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Shanley D.P.; Danielle A.W.; Manley N.R.; Palmer D.B.; et al. (2009). "An evolutionary perspective on the mechanisms of immunosenescence" (PDF). Trends in Immunology. 30 (7): 374–381. doi:10.1016/j.it.2009.05.001. PMID 19541538. <a href="https://rvc-repository.worktribe.com/preview/1642595/Equine%20Veterinary%20Journal%20-%202023%20-%20Knowles.pdf" target="_blank">https://rvc-repository.worktribe.com/preview/1642595/Equine%20Veterinary%20Journal%20-%202023%20-%20Knowles.pdf</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Shanley D.P.; Danielle A.W.; Manley N.R.; Palmer D.B.; et al. (2009). "An evolutionary perspective on the mechanisms of immunosenescence" (PDF). Trends in Immunology. 30 (7): 374–381. doi:10.1016/j.it.2009.05.001. 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Scandinavian Journal of Immunology. 22 (5): 563–75. doi:10.1111/j.1365-3083.1985.tb01916.x. PMID 4081647. S2CID 40226062. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>George A.J.; Ritter M.A. (1996). "Thymic involution with ageing: obsolescence or good housekeeping?". Immunology Today. 17 (6): 267–272. doi:10.1016/0167-5699(96)80543-3. PMID 8962629. <a href="/wiki/Immunology_Today" target="_blank">/wiki/Immunology_Today</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>Hakim F.; Memon S.; Cepeda R.; Jones E.; Chow C.; Kasten-Sportes C.; Odom J.; Vance B.; Christensen B.; et al. (2005). "Age-dependent incidence, time course, and consequences of thymic renewal in adults". Journal of Clinical Investigation. 115 (4): 930–939. doi:10.1172/JCI22492. PMC 1064981. 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