Although the thymus plays a key role in T cell maturation in mammals, begin atrophy and involution at sexual maturity. The diminished thymic microenvironment is thought to contribute to reduced adaptive immune function during aging, leading to the increased likelihood of autoimmune infectious diseases and cancer. Caloric restriction or ectopic expression of the pro-longevity growth factor fibroblast growth factor 21 has been reported to maintain the thymus in aging mice. Moreover, forced expression of the transcription factor FoxN1 has been shown to rejuvenate thymuses from old mice almost completely, restoring their youthful state. These results open the way for development of potential drugs to restore immune function in the elderly.
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References
1.
BoehmerH von. The thymus in immunity and in malignancy. Cancer Immunol Res, 2014; 2:592–597.
2.
PalmerDB. The effect of age on thymic function. Front Immunol, 2013; 4.
3.
ChengC-W, AdamsGB, PerinL, WeiM, ZhouX, LamBS, Da SaccoS, MirisolaM, QuinnDI, DorffTB, KopchickJJ. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell, 2014; 14:810–823.
YoumY-H, HorvathTL, MangelsdorfDJ, KliewerSA, DixitVD. Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. Proc Natl Acad Sci USA, 2016; 113:1026–1031.
6.
ChenL, XiaoS, ManleyNR. Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood, 2009; 113:567–574.
7.
ZookEC, KrishackPA, ZhangS, Zeleznik-LeNJ, FirulliAB, WittePL, LePT. Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells. Blood, 2011; 118:5723–5731.
8.
BredenkampN, NowellCS, BlackburnCC. Regeneration of the aged thymus by a single transcription factor. Development, 2014; 141:1627–1637.
9.
GriffithAV, FallahiM, VenablesT, PetrieHT. Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth. Aging Cell, 2012; 11:169–177.
10.
GoldbergEL, Romero-AleshireMJ, RenkemaKR, VentevogelMS, ChewWM, UhrlaubJL, SmitheyMJ, LimesandKH, SempowskiGD, BrooksHL, Nikolich‐ŽugichJ. Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell, 2015; 14:130–138.
ZhangX, YeungDCY, KarpisekM, StejskalD, ZhouZ-G, LiuF, WongRL, ChowWS, TsoAW, LamKS, XuA. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes, 2008; 57:1246–1253.
13.
ChavezAO, Molina-CarrionM, Abdul-GhaniMA, FolliF, DeFronzoRA, TripathyD. Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care, 2009; 32:1542–1546.
14.
ChenC, CheungBMY, TsoAWK, WangY, LawLSC, OngKL, WatNM, XuA, LamKS. High plasma level of fibroblast growth factor 21 is an independent predictor of type 2 diabetes A 5.4-year population-based prospective study in Chinese subjects. Diabetes Care, 2011; 34:2113–2115.
15.
Fisher ffolliottM, ChuiPC, AntonellisPJ, BinaHA, KharitonenkovA, FlierJS, Maratos-FlierE. Obesity Is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes, 2010; 59:2781–2789.
16.
BadmanMK, PissiosP, KennedyAR, KoukosG, FlierJS, Maratos-FlierE. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab, 2007; 5:426–437.
17.
GälmanC, LundåsenT, KharitonenkovA, BinaHA, ErikssonM, HafströmI, DahlinM, ÅmarkP, AngelinB, RudlingM. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metab, 2008; 8:169–174.
18.
Reis MD dosS, CsomosK, DiasLPB, ProdanZ, SzerafinT, SavinoW, TakacsL. Decline of FOXN1 gene expression in human thymus correlates with age: Possible epigenetic regulation. Immun Ageing, 2015; 12:18.
19.
RuanL, ZhangZ, MuL, BurnleyP, WangL, CoderB, ZhugeQ, SuDM. Biological significance of FoxN1 gain-of-function mutations during T and B lymphopoiesis in juvenile mice. Cell Death Dis, 2014; 5:e1457.
20.
MendelsohnAR, LarrickJW. Fibroblast growth factor-21 is a promising dietary restriction mimetic. Rejuvenation Res, 2012; 15:624–628.
