{{Short description|Involution (shrinking) of the thymus after the neonatal period}} {{Infobox medical condition (new) | name = Thymic involution | synonyms = | image = | caption = | pronounce = | field = Immunology | symptoms = shrinking of thymus | onset = | duration = | causes = | risks = | diagnosis = | differential = | prevention = | treatment = | medication = | prognosis = | frequency = | deaths = | complications = | types = }}'''Thymic involution''' is the shrinking (involution) of the thymus with age, resulting in changes in the architecture of the thymus and a decrease in tissue mass.<ref name="Shanley et al 20092">{{cite journal |author1=Shanley D.P. |author2=Danielle A.W. |author3=Manley N.R. |author4=Palmer D.B. |display-authors=etal |year=2009 |title=An evolutionary perspective on the mechanisms of immunosenescence |url=https://rvc-repository.worktribe.com/preview/1642595/Equine%20Veterinary%20Journal%20-%202023%20-%20Knowles.pdf |journal=Trends in Immunology |volume=30 |issue=7 |pages=374–381 |doi=10.1016/j.it.2009.05.001 |pmid=19541538}}</ref> Thymus involution is one of the major characteristics of vertebrate immunology, and occurs in almost all vertebrates, from birds, teleosts, amphibians to reptiles, although the thymi of a few species of sharks are known not to involute.<ref name="Shanley et al 20092" /><ref name="Zakharova 20092">{{cite journal |author=Zakharova L.A. |year=2009 |title=Evolution of adaptive immunity |url= |journal=Izvestiia Rossiĭskoĭ Akademii Nauk. Seriia Biologicheskaia |volume=2 |issue=2 |pages=143–154 |pmid=19391473}}</ref> This process is genetically regulated, with the nucleic material responsible forming an example of a conserved sequence — one maintained through natural selection (though the pressures shaping this are unclear as will be discussed) since it arose in a common ancestor of all species now exhibiting it, via a phenomenon known to bioinformaticists as an orthologic sequence homology.
T-cells are named for the thymus where T-lymphocytes migrate from bone marrow to mature. Its regression has been linked to a reduction in immunosurveillance<ref name="Linton & Dorshkind 20042">{{cite journal |author1=Linton P.J. |author2=Dorshkind K. |year=2004 |title=Age-related changes in lymphocyte development and function |url= |journal=Nature Immunology |volume=5 |issue=2 |pages=133–139 |doi=10.1038/ni1033 |pmid=14749784 |s2cid=12485241}}</ref> and the rise of infectious disease and cancer incidence in the elderly (in some cases risk is inversely proportional to thymus size).<ref name="Palmer et al. 20182">{{cite journal |author1=Palmer S. |author2=Albergante L. |author3=Blackburn C.C. |author4=Newman T.J. |year=2018 |title=Thymic involution and rising disease incidence with age |url= |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=115 |issue=8 |pages=1883–1888 |bibcode=2018PNAS..115.1883P |doi=10.1073/pnas.1714478115 |pmc=5828591 |pmid=29432166 |doi-access=free}}</ref> Though thymic involution has been linked to immunosenescence, it is not induced by senescence as the organ starts involuting from a young age:<ref name="Taub & Long 20052">{{cite journal |author1=Taub D.D. |author2=Long D.L. |year=2005 |title=Insights into thymic aging and regeneration |url= |journal=Immunological Reviews |volume=205 |issue= |pages=72–93 |doi=10.1111/j.0105-2896.2005.00275.x |pmid=15882346 |s2cid=24461464}}</ref> in humans, as early as the first year after birth.<ref name="Steinmann et al 19852">{{cite journal |author1=Steinmann G.G. |author2=Klaus B. |author3=Muller-Hermelin H.K. |display-authors=etal |year=1985 |title=The involution of the aging human thymic epithelium is independent of puberty. A morphometric study |url= |journal=Scandinavian Journal of Immunology |volume=22 |issue=5 |pages=563–75 |doi=10.1111/j.1365-3083.1985.tb01916.x |pmid=4081647 |s2cid=40226062}}</ref>
== Progression == === Neonatal period === Though the thymus is fully developed before birth,<ref name="Parham 20052">Parham, P. 2005. The immune system: Second edition Garland Science.</ref> newborns have an essentially empty peripheral immune compartment immediately after birth.<ref name="Min et al 20032">{{cite journal |author1=Min B. |author2=McHugh R. |author3=Sempowski G.D. |author4=Mackall C. |author5=Foucras G. |author6=Paul W.E. |display-authors=etal |year=2003 |title=Neonates support lymphopenia-induced proliferation |url= |journal=Immunity |volume=18 |issue=1 |pages=131–140 |doi=10.1016/S1074-7613(02)00508-3 |pmid=12530982 |doi-access=free}}</ref><ref name="Schuler et al 20042">{{cite journal |author1=Schuler T. |author2=Hammerling G.J. |author3=Arnold B. |display-authors=etal |year=2004 |title=Cutting edge: IL-7-dependent homeostatic proliferation of CD8+ T cells in neonatal mice allows the generation of long-lived natural memory T cells |url= |journal=Journal of Immunology |volume=172 |issue=1 |pages=15–19 |doi=10.4049/jimmunol.172.1.15 |pmid=14688303 |doi-access=free}}</ref> Hence, T lymphocytes are not present in the peripheral lymphoid tissues, where naïve, mature lymphocytes are stimulated to respond to pathogens. In order to populate the peripheral system, the thymus increases in size and upregulates its function during the early neonatal period.<ref name="Shanley et al 20092" />
=== Age-relatedness === Though some sources{{which|date=May 2020}} cite puberty as the time of onset, other studies have reported thymic involution to start much earlier.<ref name="Shanley et al 20092" /> 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).<ref name="Steinmann et al 19852" /> 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.<ref name="Steinmann et al 19852" /> Accordingly, the thymus should stop functioning at around 105 years of age;<ref name="George & Ritter 19962">{{cite journal |author1=George A.J. |author2=Ritter M.A. |year=1996 |title=Thymic involution with ageing: obsolescence or good housekeeping? |url= |journal=Immunology Today |volume=17 |issue=6 |pages=267–272 |doi=10.1016/0167-5699(96)80543-3 |pmid=8962629}}</ref> but, studies with bone marrow transplant patients have shown that the thymi of the majority of patients over forty were unable to build a naïve T cell compartment.<ref name="Hakim et al 20052">{{cite journal |author1=Hakim F. |author2=Memon S. |author3=Cepeda R. |author4=Jones E. |author5=Chow C. |author6=Kasten-Sportes C. |author7=Odom J. |author8=Vance B. |author9=Christensen B. |display-authors=etal |year=2005 |title=Age-dependent incidence, time course, and consequences of thymic renewal in adults |url= |journal=Journal of Clinical Investigation |volume=115 |issue=4 |pages=930–939 |doi=10.1172/JCI22492 |pmc=1064981 |pmid=15776111}}</ref>
With both qualitative and quantitative changes to thymus production occurring with age, 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.<ref>{{cite journal |last1=Gui |first1=J. |last2=Mustachio |first2=L. M. |last3=Su |first3=D. M. |last4=Craig |first4=R. W. |date=2012 |title=Thymus Size and Age-related Thymic Involution: Early Programming, Sexual Dimorphism, Progenitors and Stroma |journal=Aging and Disease |volume=3 |issue=3 |pages=280–290 |pmc=3375084 |pmid=22724086}}</ref>
== Effects == The ability of the immune system to mount a strong protective response depends on the receptor diversity of naive T cells (TCR). Thymic involution results in a decreased output of naïve T lymphocytes – mature T cells that are tolerant to self antigens, responsive to foreign antigens, as yet 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.<ref name="Naylor et al 20052">{{cite journal |author1=Naylor K. |author2=Li G. |author3=Vallejo A.N. |author4=Lee W.W. |author5=Koetz K. |author6=Bryl E. |author7=Witkowski J. |author8=Fulbright J. |author9=Weyand C.M. |display-authors=etal |year=2005 |title=The influence of age on T cell generation and TCR diversity |url= |journal=Journal of Immunology |volume=174 |issue=11 |pages=7446–7452 |doi=10.4049/jimmunol.174.11.7446 |pmid=15905594 |doi-access=free}}</ref> For as yet unknown reasons, TCR diversity drops drastically around age 65.<ref name="Naylor et al 20052" /> Loss of thymic function and TCR diversity is thought to contribute to weaker immune function in the elderly, including increasing instances of diseases such as cancers, autoimmunity, and opportunistic infections.<ref name="Lynch et al 20092">{{cite journal |author1=Lynch H.E. |author2=Goldberg G.L. |author3=Chidgey A. |author4=Boyd R. |author5=Sempowski G.D. |display-authors=etal |year=2009 |title=Thymic involution and immune reconstitution |url= |journal=Trends in Immunology |volume=30 |issue=7 |pages=366–373 |doi=10.1016/j.it.2009.04.003 |pmc=2750859 |pmid=19540807}}</ref>
=== Acute involution and treatment implications === Growing evidence indicates that thymic involution is plastic and can be therapeutically halted/reversed to help boost the immune system. Under certain circumstances, the thymus has been shown to undergo acute thymic involution (alternatively called transient involution).<ref name="Shanley et al 20092" /> For example, transient involution has been induced in humans and other animals by stressors<ref name="Dominguez-Gerpe & Rey-Mendez 19972">{{cite journal |author1=Dominguez-Gerpe L |author2=Rey-Mendez M |year=2003 |title=Evolution of the Thymus Size in Response to Physiological and Random Events Throughout Life |url= |journal=Microscopy Research and Technique |volume=62 |issue=6 |pages=464–476 |doi=10.1002/jemt.10408 |pmid=14635139 |s2cid=45341750 |doi-access=free}}</ref> such as infections,<ref name="Savino 20062">{{cite journal |author=Savino W |year=2006 |title=The thymus is a common target organ in infectious diseases |url= |journal=PLOS Pathogens |volume=2 |issue=6 |pages=472–483 |doi=10.1371/journal.ppat.0020062 |pmc=1483230 |pmid=16846255 |doi-access=free}}</ref><ref name="Savino et al 20072">{{cite journal |author1=Savino W |author2=Dardenne M |author3=Velloso LA |author4=Silva-Barbosa SD |year=2007 |title=The thymus is a common target in malnutrition and infection |url= |journal=British Journal of Nutrition |volume=98 |issue= |pages=S11–S16 |doi=10.1017/s0007114507832880 |pmid=17922946 |doi-access=free}}</ref> pregnancy,<ref name="Kendall & Clarke 20002">{{cite journal |author1=Kendall M.D. |author2=Clarke A.G. |year=2000 |title=The thymus in the mouse changes its activity during pregnancy: a study of the microenvironment |url= |journal=Journal of Anatomy |volume=197 |issue=3 |pages=393–411 |doi=10.1046/j.1469-7580.2000.19730393.x |pmc=1468141 |pmid=11117626}}</ref> and malnutrition.<ref name="Savino et al 20072" /><ref name="Cromi ''et al.'' 20092">{{cite journal |author1=Cromi A. |author2=Ghezzi F. |author3=Raffaelli R. |author4=Bergamini V. |author5=Siesto G. |author6=Bolis P. |display-authors=etal |year=2009 |title=Ultrasonographic measurement of thymus size in IUGR fetuses: a marker of the fetal immunoendocrine response to malnutrition |url= |journal=Ultrasound in Obstetrics & Gynecology |volume=33 |issue=4 |pages=421–426 |doi=10.1002/uog.6320 |pmid=19306477 |s2cid=5473679 |doi-access=free}}</ref><ref name="Howard et al 19992">{{cite journal |author1=Howard J.K. |author2=Lord G.M. |author3=Matarese G. |author4=Vendetti S. |author5=Ghatei M.A. |author6=Ritter M.A. |author7=Lechler R.I. |author8=Bloom S.R. |display-authors=etal |year=1999 |title=Leptin protects mice from starvation induced lymphoid atrophy and increases thymic cellularity in ob/ob mice |url=http://spiral.imperial.ac.uk/bitstream/10044/1/60/1/Leptin%20protects%20mice%20from.pdf |journal=Journal of Clinical Investigation |volume=104 |issue=8 |pages=1051–1059 |doi=10.1172/JCI6762 |pmc=408574 |pmid=10525043}}</ref> The thymus has also been shown to decrease during hibernation and, in frogs, change in size depending on the season, growing smaller in the winter.<ref name="Wtytycz et al 19962">Wytycz, B., Mica, J., Jozkowir, A. & Bigaj J. 1996. Letters: Plasticity of thymuses of ectothermic vertebrates. Immunology Today (Comment). 442: No.9.</ref> Studies on acute thymic involution may help in developing treatments for patients, who for example are unable to restore immune function after chemotherapy, ionizing radiation, or infections like HIV.<ref name="Lynch et al 20092" /> Research has reported the rate of thymus involution to reduce when, for men the testes, or for women the ovaries, were removed; demonstrating that sex hormones, and especially testosterone, have a marked influence on the involution process. However, the manner in which the sex hormones moderate this process is not fully understood. In other research the results of the Greg Fahy TRIIM trial reported clinically significant reversal of thymus involution after the administration of human growth hormone (HGH), Dehydroepiandrosterone (DHEA) and metformin.<ref>{{Cite web |title=Reversing Thymic Involution – Intervene Immune |url=http://interveneimmune.com/?page_id=1131 |access-date=2020-12-31 |language=en-US}}</ref> The two results could mean that HGH and mTOR inhibition in autophagy reverses thymus involution with testosterone advancing thymus involution.<ref>{{Cite journal |last1=Sutherland |first1=Jayne S. |last2=Goldberg |first2=Gabrielle L. |last3=Hammett |first3=Maree V. |last4=Uldrich |first4=Adam P. |last5=Berzins |first5=Stuart P. |last6=Heng |first6=Tracy S. |last7=Blazar |first7=Bruce R. |last8=Millar |first8=Jeremy L. |last9=Malin |first9=Mark A. |last10=Chidgey |first10=Ann P. |last11=Boyd |first11=Richard L. |date=2005-08-15 |title=Activation of Thymic Regeneration in Mice and Humans following Androgen Blockade |url=https://www.jimmunol.org/content/175/4/2741 |journal=The Journal of Immunology |language=en |volume=175 |issue=4 |pages=2741–2753 |doi=10.4049/jimmunol.175.4.2741 |issn=0022-1767 |pmid=16081852 |doi-access=free}}</ref> Additionally, caloric restriction has been shown to lessen thymic involution due to aging in mice.<ref>{{Cite journal |last=Liang |first=Zhanfeng |last2=Dong |first2=Xue |last3=Zhang |first3=Zhaoqi |last4=Zhang |first4=Qian |last5=Zhao |first5=Yong |date=2022 |title=Age-related thymic involution: Mechanisms and functional impact |url=https://onlinelibrary.wiley.com/doi/abs/10.1111/acel.13671 |journal=Aging Cell |language=en |volume=21 |issue=8 |doi=10.1111/acel.13671 |issn=1474-9726 |pmc=9381902 |pmid=35822239 |article-number=e13671}}</ref>
== Unknown selective pressures == Thymic involution remains an evolutionary mystery since it occurs in most vertebrates despite its negative effects.
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:
* Developing T cells that interact strongly 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 presented within the thymus is truly of self origin, but antigens from pathogenic microbes that infiltrate the thymus have the potential to subvert the 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, generally when organisms are young and under the protection of a functional maternal immune system.<ref>{{cite journal |author=Turke P |year=1995 |title=Microbial parasites versus developing T cells: an evolutionary arms race with implications for the timing of thymic involution and HIV pathenogenesis |url= |journal=Thymus |volume=24 |issue=1 |pages=29–40 |pmid=8629277}}</ref> Thus, in mice and humans, for example, the best time to have a prodigiously functional thymus is prior to birth.
: In turn, it is well known from Williams'<ref>{{cite journal |author=Williams G. C. |year=1957 |title=Pleiotropy, natural selection, and the evolution of senescence |url= |journal=Evolution |volume=11 |issue=4 |pages=398–411 |doi=10.2307/2406060 |jstor=2406060}}</ref> theory of the evolution of senescence that strong selection for enhanced early function readily accommodates, through ''antagonistic pleiotropy'', deleterious later occurring effects, thus potentially accounting for the especially early demise of the thymus.
* The ''disposable soma hypothesis'' and ''life history hypothesis'' 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.<ref name="Shanley et al 20092" /> * Other hypotheses suggest that thymic involution is ''directly'' adaptive. For example, some hypotheses have proposed that thymic involution may help in avoidance of autoimmunity or other dangers,<ref name="Aronson 19912">{{cite journal |author=Aronson M |year=1991 |title=Hypothesis: involution of the thymus with aging–programmed and beneficial |url= |journal=Thymus |volume=18 |issue=1 |pages=7–13 |pmid=1926291}}</ref> prevention of infection,<ref name="George & Ritter 19962" /> and production of an optimal repertoire of T-cells.<ref name="Dowling & Hodgkin 20092">{{cite journal |author1=Dowling M.R. |author2=Hodgkin P.D. |year=2009 |title=Why does the thymus involute? A selection-based hypothesis |url= |journal=Trends in Immunology |volume=30 |issue=7 |pages=295–300 |doi=10.1016/j.it.2009.04.006 |pmid=19540805}}</ref> * ''Zinc deficiency'' may also play a role.<ref>{{cite journal |vauthors=Mocchegiani E, Muzzioli M, Cipriano C, Giacconi R |year=1998 |title=Zinc, T-cell pathways, aging: role of metallothioneins |journal=Mechanisms of Ageing and Development |volume=106 |issue=1–2 |pages=183–204 |doi=10.1016/S0047-6374(98)00115-8 |pmid=9883983 |s2cid=43299065}}</ref>
== References == <references responsive="1"></references>
== External links == {{spoken Wikipedia|date=May 5th, 2020|thymic involution.ogg}} category:thymus category:ageing processes