Aging Cell. 2020;19:e13260.
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1 o 25
h ps://doi.o g/10.1111/acel.13260
wileyonlinelib a y.com/jou nal/acel
1 | INTRODUCTION
Thy oid ho mone (TH) p oduc ion is a igh ly egula ed p ocess
con olled by a classic nega i e eedback loop in ol ing he hy-
po halamus, he pi ui a y, and he hy oid, which has led o he
common name hypo halamus–pi ui a y– hy oid axis (Figu e 1).
The hy o opin- eleasing ho mone (TRH) is p oduced in he
hypo halamus. Once eleased, TRH eaches he pi ui a y gland
and binds o he TRH ecep o and s imula es he p oduc ion
and sec e ion o hy oid-s imula ing ho mone (TSH), also known
as hy o opin (Liu e al., 2019). In he hy oid, TSH binds o he
TSH ecep o (TSHR) and induces TH p oduc ion. When needed,
Recei ed:24Ap il2020
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Re ised:27July2020
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Accep ed:13Sep embe 2020
DOI: 10.1111/acel.13260
REVIEW
Thy oid ho mones in diabe es, cance , and aging
Benoi R. Gau hie 1,2 | Alejand o Sola-Ga cía1 | Ma ía Ángeles Cáliz-Molina1 |
Pe a Isabel Lo enzo1 | Nadia Cobo-Vuilleumie 1 | Vi ian Capilla-González1 |
Alejand o Ma in-Mon al o1
This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion License, which pe mi s use, dis ibu ion and ep oduc ion in any medium,
p o ided he o iginal wo k is p ope ly ci ed.
© 2020 The Au ho s. Aging Cellpublishedby heAna omicalSocie yandJohnWiley&SonsL d.
1Depa men o Cell The apy and
Regene a ion, Andalusian Cen e o
Molecula Biology and Regene a i e
Medicine-CABIMER,Jun adeAndalucía-
Uni e si y o Pablo de Ola ide-Uni e si y
o Se ille-CSIC, Se ille, Spain
2Biomedical Resea ch Ne wo k on
Diabe es and Rela ed Me abolic Diseases-
CIBERDEM, Ins i u o de Salud Ca los III,
Mad id, Spain
Co espondence
Alejand o Ma in-Mon al o, Depa men
o Cell The apy and Regene a ion,
Andalusian Cen e o Molecula Biology
and Regene a i e Medicine-CABIMER,
Jun adeAndalucía-Uni e si yo Pablode
Ola ide-Uni e si y o Se ille-CSIC, Se ille
41092, Spain.
Email: alejand o.ma inmon al o@cabime .
es
FUNDING INFORMATION
The au ho s ecei e inancial suppo
om he Ins i u e o Heal h Ca los III
and he Spanish Minis y o Science,
Inno a ion and Uni e si y, co- unded by
Fondos FEDER/Fondo social Eu opeo
(PI18/01590 and CPII19/00023 o A.M-M;
CP19/00046 o V.C-G, FI19/00162 o
ASG,andBFU2017-83588-P oBRG), he
Andalusian Regional Minis y o Heal h
(C2-0024-2019 oA.M-MandPI-0272-
2017 oV.C-G).
Summa y
Thy oid unc ion is cen al in he con ol o physiological and pa hophysiological p o-
cesses. S udies in animal models and human esea ch ha e de e mined ha hy oid
ho mones modula e cellula p ocesses ele an o aging and o he majo i y o age-
ela ed diseases. While se e al s udies ha e associa ed mild educ ions on hy oid
ho mone unc ion wi h excep ional longe i y in animals and humans, al e a ions in
hy oid ho mones a e se ious medical condi ions associa ed wi h unheal hy aging and
p ema u e dea h. Mo eo e , bo h hype hy oidism and hypo hy oidism ha e been as-
socia ed wi h he de elopmen o ce ain ypes o diabe es and cance s, indica ing
a g ea complexi y o he molecula mechanisms con olled by hy oid ho mones. In
his e iew, we desc ibe he la es indings in hy oid ho mone esea ch in he ield o
aging, diabe es, and cance , wi h a special ocus on hepa ocellula ca cinomas. While
aging s udies indica e ha he di ec modula ion o hy oid ho mones is no a iable
s a egy o p omo e heal hy aging o longe i y and he de elopmen o hy omime -
ics is challenging due o ine icacy and po en ial oxici y, we a gue ha in e en ions
based on he use o modula o s o hy oid ho mone unc ion migh p o ide he apeu-
ic bene i in ce ain ypes o diabe es and cance s.
KEYWORDS
cance , diabe es, heal h span, hype hy oidism, hypo hy oidism, li e span, hy oid ho mones
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GAUTHIER ET Al.
iiodo hy onine (T3) and e aiodo hy onine (T4), also known as
hy oxine, a e eleased in o he ci cula ion. In he hypo halamus
and he pi ui a y, THs ac ia he nuclea TH ecep o β (THRβ)
o inhibi TRH and TSH p oduc ion and sec e ion, comple ing a
nega i e eedback loop ha main ains he physiological le els o
TRH, TSH, and THs.
In a ge cells, deiodinases (DIO2 and DIO3) gene a e T3 om
T4 by emo ing he iodine loca ed a he 5′ posi ion o T4. The
FIGURE 1 Schemesumma izingTHsyn hesis.TRHisp oducedbyaspeci icg oupo neu onsloca edin hepa a en icula nucleus
o he hypo halamus. When TRH eaches he pi ui a y gland, i binds o he TRH ecep o exp essed in he hy o ophs, s imula ing he
exp ession and sec e ion o TSH in o he ci cula ion. TSH eaches he hy oid gland and binds o he TSHR loca ed in he cell memb ane o
he hy oid ollicles,se inginmo ionTHp oduc ioninap ocess ha includes heinduc iono iodineup akeby heNIS.Iodideismobilized
o hecolloid iaPend inac ion,andi is henoxidizedby he hy oidpe oxidase(TPO)usingH2O2. Iodina ion o y osine esidues o ms
monoiodo y osines and diiodo y osines ha a e coupled o o m T3 and T4. T3 and T4 bound o TG a e eleased in he colloid o he
ollicle.Whenneeded,iodina edTGisca abolizedin hy oid ollicula epi helialcells op oduceT3andT4,whicha e hen eleasedin o he
ci cula ion. In he bloods eam, THs can be ound ei he ee o bound o se um TH-binding p o eins (STHBP), such as hy oxine-binding
p o ein, ans hy e in, and albumin. F ee THs a e able o en e in o a ge cells in a ge issues ia memb ane anspo e s. In a ge cells,
deiodinases gene a e T3 om T4 by emo ing he iodine loca ed a he 5´ posi ion o T4. In acellula T3 ac s ia genomic ac ions binding
o he THR, whe e modula e gene exp ession, o ia non-genomic ac ions a ec ing signaling pa hways such as in eg in α β3 and PI3 K. THs
also ac ia he nuclea THRβ in he hypo halamus and he pi ui a y o inhibi TRH and TSH p oduc ion and sec e ion, comple ing a nega i e
eedback loop ha main ains physiological le els o THs. DIO: deiodinase. DUOX2: dual oxidase 2. DUOXA2: dual oxidase ma u a ion
ac o 2. I−: iodide. STHBP: se um TH-binding p o eins. Na+: sodium. NIS: sodium-iodide sympo e . T3: iiodo hy onine. T4: hy oxine. Tg:
hy oglobulin. TH: hy oid ho mone. THR: hy oid ho mone ecep o s. TPO: hy oid pe oxidase. TRH: hy o opin- eleasing ho mone. TSH:
hy o opin. TSHR: hy o opin ecep o
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3 o 25GAUTHIER ET Al.
exp ession o he di e en deiodinases is cell- ype and issue-spe-
ci ic, which p o ides a mechanism o con ol TH ac ions i espec-
i eo ci cula ingTHle els(Ge ebene al.,2008;Schweize e al.,
2008). In acellula T3 ac s ia binding o he TH ecep o α (THRα)
and THRβ, which display high a ini y o DNA sequences called
TH esponse elemen s (TREs). Upon ligand binding, THRs assemble
in o a co-ac i a o complex wi h his one ace yl ans e ase ac i -
i y ha is ec ui ed os imula e ansc ip ion(Lona d&O'Malley,
2007;Pe issie al.,2010).Mo eo e ,THRin e ac swi ho he nu-
clea ho mone ecep o s, such as pe oxisome p oli e a o -ac i a ed
ecep o s, e inoid X ecep o s, e inoic acid ecep o s, and li e X
ecep o s ha allow binding o a wide epe oi e o nucleo ide se-
quences ha con ibu e o egula e di e en me abolic pa hways,
including choles e ol, glucose, and a y acid me abolism in di e en
issues(B en ,2012;Kouidhi&Cle ge -F oide aux,2018).Inaddi-
ion, THs also modula e molecula pa hways ia p o ein–p o ein in-
e ac ionssuchasPI3K-AKT-FOXO1andmTOR-p70S6Ksignaling,
which u he modula e ansc ip ion (Cao e al., 2005; Da is e al.,
2016;Flaman e al.,2017;Mullu e al.,2014).In hep esenceo ab-
sence o THs, THRs modula e he exp ession o mo e han 80 genes,
mainly in ol ed in mi ochond ial biogenesis, oxida i e phospho y-
la ion, ica boxylic acid cycle, de no o lipogenesis, and a y acid
ca abolism(Flo es-Mo alese al.,2002;Jackson-Hayese al.,2003;
Singh e al., 2018). O e all, THs enhance oxygen consump ion and
ATP hyd olysis and educe he coupled s a e o he mi ochond ia
inducing heca abolismo all ypeso ene gysou ces(Johannsen
e al., 2012; Weins ein e al., 1991). A he o ganismic le el, THs in-
c ease he basal me abolic a e, which is de ined as a e o ene gy
expendi u e pe ime a es .
THs a e equi ed o he de elopmen and ma u a ion o se e al
issuesandgene alwell-being(Nge al.,2013;Nuneze al.,2008).
Hollowell e al. ha e de ined he no mal e e ence anges o o al T4 a
57.9–169.9nMandTSHa 0.39–4.6mIU/L(Figu e2)(Hollowelle al.,
2002). I is es ima ed ha in he gene al popula ion he p e alence o
TH al e a ions is ~0.5%–4% in a eas wi h su icien iodine exposu e.
The e a e di e en ypes o TH al e a ions (hype hy oidism, subclini-
cal hype hy oidism, subclinical hypo hy oidism, and hypo hy oidism)
ha lead o di e en clinical symp oms (Figu e 2) (Hollowell e al.,
2002). Recen epidemiological me a-analyses ha e de e mined a clea
associa ion o TH al e a ions wi h mo ali y isk in he gene al pop-
ula ion (B and e al., 2011; Ko a e al., 2015; Th ilum e al., 2012).
Clinical hypo hy oidism, also known as o e hypo hy oidism, is
associa ed wi h me abolic de egula ions, such as hype choles e ol-
emia, and inc eased low-densi y lipop o ein (LDL) le els, ha inc ease
he isk o de eloping diabe es melli us (DM) and ca dio ascula com-
plica ions(Cappola&Ladenson,2003;Dun as,2002;Gaoe al.,2013;
Sawin e al., 1985; Taylo e al., 2013; Wang e al., 2012). Subclinical
hypo hy oidism has also been associa ed wi h se ious complica ions
such as imp ope neu ocogni i e heal h, unbalanced bone me abo-
lism, p opensi y o de elop ype 2 DM (T2DM), ca dio ascula -asso-
cia ed isk ac o s, such as high LDL and e y-low-densi y lipop o ein
(VLDL) le els, hype iglyce idemia, hype ension, a ial ib illa ion,
and obesi y, as well as low le els o high-densi y lipop o ein (HDL) and
p ema u emo ali y(Aue e al.,2001;Biondi&Coope ,2008;Biondi
e al., 2002; Ce esini e al., 2013; Han e al., 2015; Pea ce, 2012; Taylo
e al., 2013). On he o he side o he spec um, hype hy oid indi-
iduals also ha e inc eased isk o de eloping DM and ca dio ascula
complica ions ha can cause p ema u e dea h (B and e al., 2013;
F anklyn e al., 2005). Howe e , ca dio ascula complica ions a e
no associa ed wi h hype choles e olemia in hype hy oid pa ien s,
and hey no mally exhibi educed ci cula ing choles e ol le els (Kim
e al., 2020). In he case o subclinical hype hy oidism wi h se e ely
dec eased TSH, clinical da a indica e an inc eased incidence o de-
men iaandneu ocogni i edys unc ion(Aube e al.,2017;Benseno
e al., 2010). O e hype hy oidism and e en subclinical hype hy-
oidism inc ease he isk o bone ac u es (Blum e al., 2015; Nicholls
e al.,2012;Ves e gaa d&Mosekilde,2003).Al oge he ,clinicalda a
clea ly indica e ha in he gene al popula ion TH al e a ions a e asso-
cia ed wi h poo quali y o li e.
1.1 | Thy oid ho mones in aging
1.1.1 | The egula ion o hy oid ho mones in
aging and hei ole in longe i y
Ea ly obse a ions ha e es ablished ha es ic ed hy oid unc-
ion is associa ed wi h longe li e span in small and la ge mammals,
FIGURE 2 Re e ence angesandmedicalcondi ionsassocia ed
wi h hy oid dys unc ion. This igu e de ines e e ence anges
o p ima y hypo hy oidism, seconda y hypo hy oidism, e ia y
hypo hy oidism, subclinical hypo hy oidism, eu hy oidism,
subclinical hype hy oidism, p ima y hype hy oidism/ hy oxine
in oxica ion, and TSH-p oducing adenoma/ esis ance o THs. TSH
and T4 le els we e de ined as Hollowell e al. To al hy oxine can
becon e ed omnM oµg/dl,di idingby12.87.THs: hy oid
ho mones. TSH: hy o opin
noi a necnoc4Tla oT
TSH concen a ion
P ima y
hype hy oidism
o hy oxine
in oxica ion
P ima y
hypo hy oidism
0.1 mIU/L4.5 mIU/L
57.9 nM
169.9 nM
Eu hy oidism
TSH-p oducing adenoma
o esis ance o THs
Subclinical
hype hy oidism
Subclinical
hypo hy oidism
Secunda y o e ia y
hypo hy oidism (abno mal
hypo halamus o pi ui a y unc ion)
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GAUTHIER ET Al.
includinghumans(Bowe se al.,2013;Bu ens ein&Pin o,2009;
Jansen,e al.,2015).Acco dingly,highe se umTSHle elsand/o
low se um ee T4 le els ha e been associa ed wi h longe li e expec-
ancy, indica ing an impo an ole o THs in aging (Beld e al., 2005;
Gusseklooe al.,2004,2006;Rozing,e al.,2010).Al houghaging
may no be conside ed a disease, i can be a gued ha he aging
p ocess is no a homogeneous physiological p ocess. F om an e o-
lu iona ypoin o iew,na u alselec ionop imizesmechanismsand
p ocesses ha allow unc ionali y and su i al un il he end o he
ep oduc i e li e. Howe e , a pos - ep oduc i e age in he majo i y
o species, he e is li le na u al selec ion o igh agains mecha-
nisms ha p oduce unheal hy aging and dea h. No wi hs anding, in
ce ain species such as humans, whe e amilial and social in e ac-
ions can be ele an o he su i al o young indi iduals, na u al
selec ion migh s ill ha e a signi ican ole o p omo e longe i y
(Tully&Lambe ,2011).Gi en hesein e es ing ac s,i isdi icul
o de ine whe he changes ha occu in hy oid unc ion in aged
indi iduals a e adap i e o maladap i e.
Al hough T4 sec e ion has been shown o be sligh ly educed
inagedindi iduals, hecapaci y ome abolizeT4bydeiodina ion
media ed by DIO1 and DIO2 is dec eased in ce ain issues o aged
indi iduals, and heal hy aged indi iduals exhibi no mal T4 le els
(Dun as,2018;Mazzoccolie al.,2010;Michalakise al.,2013).In his
line, old a s exhibi ing compa able TSH le els o young ones ha e
lowe DIO1 ac i i y and sepa a ed s udies in oden s ha e demon-
s a ed ha hepa ic le els o he TH anspo e MCT8 a e educed
in aged indi iduals, indica ing ha TH esponsi eness changes wi h
ad ancingage(Chake e al.,2018;Donda&Lema chand-Be aud,
1989). Mo eo e , he e a e e idences indica ing ha THs migh ha e
educed capaci y o ac i a e ce ain pos - ecep o mechanisms o
hy oid unc ion in aged indi iduals (Mo ley, 2003).
The incidence o bo h hype hy oidism and hypo hy oidism
in he olde popula ion has con inuously isen in he pas decades
(Boelae ,2013;Dun as,2018;Su ks&Hollowell,2007).Thediag-
nosis o hypo hy oidism in elde lies is di icul since olde people
exhibi milde and ewe symp oms o TH de egula ion. Mo eo e ,
symp oms expe ienced in hese pa ien s a e eadily in e p e ed as
signs o he aging p ocess, such as a igue and neu ological diso de s,
whichdi icul hediagnosiso heseal e a ions(Ma inez-Iglesias,
Ga cia-Si a, Regade a, e al., 2009). P e alence o subclinical hy-
po hy oidisma ec s~6%o hepopula ionagedbe ween70and
79yea s, isingup o10%inindi idualsagedo e 80yea s(Boelae ,
2013; Simonsick e al., 2009). No ewo hy, despi e he associa ion o
subclinical hypo hy oidism wi h se e al se ious diseases and o e all
mo ali y in he gene al popula ion, a s udy ocused on olde indi id-
uals wi h subclinical hypo hy oidism has e u ed hese associa ions
(Simonsick e al., 2009). Ac ually, epidemiological s udies in humans
ha e e en associa ed subclinical hypo hy oidism wi h a educed isk
o all-cause mo ali y in indi iduals olde han 65 yea s o age (Selme
e al., 2014). Fu he mo e, se e al epo s ha e indica ed ha old in-
di iduals,o a leas 70yea so agediagnosedwi hsubclinicalhypo-
hy oidism (TSH le els in he ange o 4.5–10.0 mIU/L), migh e en
ha e ce ain physical unc ion ad an ages and lowe mo ali y when
compa ed o indi iduals wi h no mal hy oid unc ion (Simonsick
e al., 2009, 2016). Suppo ing he p o-longe i y bene i s o educed
hy oid unc ion in he elde ly, hy oxine eplacemen he apy was
no e icien in imp o ing cogni i e unc ion in old pa ien s wi h sub-
clinical hypo hy oidism (Pa k e al., 2010).
The p e alence o hype hy oidism in indi iduals olde han
60yea s anges om1% o15%(Bannis e &Ba nes,1989;Chio a o
e al.,1997;Samuels&Feingold,2000),beingau oimmuneG a es’
disease is he mos common e iology o hype hy oidism in aged indi-
iduals. The majo i y o p ospec i e s udies associa e highe TH con-
cen a ions wi h inc eased ail y and dec eased unc ional capaci y
in old pa ien s (Ce esini e al., 2011; Chake e al., 2018; Simonsick
e al., 2009). In his line, low le els o TSH o ele a ed le els o ee T4
ha e been linked o comp omised quali y o li e and inc eased mo al-
i y isk in he aged popula ion (Gussekloo e al., 2004, 2006; K ame
e al., 2009; Pa le e al., 2001; Singe , 2006; Wa ing, e al., 2012). The
p o-aging e ec s o THs ha e been s udied and ac i e T3 binding o
he THRβ iso o m is known o p oduce DNA damage and p ema u e
senescence, making a causal connec ion wi h molecula p ocesses o
accele a ed aging (Zamb ano e al., 2014). Mo eo e , he de imen al
e ec s o ch onic hype hy oidism in li e expec ancy ha e been ob-
se edinmiceand a s(Lopez-No iegae al.,2019;Ooka&Shinkai,
1986). In his sense, wild- ype mice exposed o T4 leading o a wo old
inc ease in ci cula ing T4 le els exhibi an ~50% educ ion in mean and
maximalli espan(Lopez-No iegae al.,2019).
Se e al s udies ha e indica ed ha di e en TH le els wi hin he
no mal ange could also ha e physiological ele ance. In his ega d,
high–no mal ee T4 le els a e conside ed a isk ac o o poo ou -
comes o ca dio ascula disease and mo ali y (Hoge o s e al.,
2008; Simonsick e al., 2016). Se e al epo s ha e de e mined he
e ec o a ia ions o TH le els wi hin eu hy oidism on gai speed
in olde people, indica ing ha highe TH le els a e associa ed wi h
slowe gai speed (Bano, e al., 2016; Chake e al., 2018; Simonsick
e al., 2016). Rema kably, da a in he li e a u e indica e ha subjec s
wi h low–no mal ee T4 le els o wi h high–no mal TSH le els we e
expec ed oli eup o3.7yea slonge hanindi idualswi hhigh–
no mal ee T4 le els o low–no mal TSH le els (Bano e al., 2019;
Chake e al., 2018). Mo eo e , lowe ee T4 le els ha e been asso-
cia ed wi h be e unc ional mobili y and i ness in heal hy eu hy-
oidindi idualswi hages anging om68 o97yea s,whichhasled
o p opose low–no mal ee T4 le els as a ma ke o heal hy aging
(Rozinge al.,2010;Rozinge al.,2010;Simonsicke al.,2016).In
his line, lowe me abolic cos o walking in adul s is associa ed wi h
g ea e gai speed and a slowe decline (Sch ack e al., 2012, 2016).
O e all, hese da a a e in ag eemen wi h he a e o li ing heo y
o aging, sugges ing ha a lowe me abolic demand p edisposes o
longe heal h span and li e span.
1.2 | The special case o cen ena ians
The e is s ong e idence indica ing ha a gene ic componen p e-
disposes o longe i y, which is suppo ed by s udies indica ing ha
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5 o 25GAUTHIER ET Al.
long-li ed pa en s ha e long-li ed o sp ing (Gudmundsson e al.,
2000; Ke be e al., 2001; Rozing, e al., 2010). Indi iduals wi h
excep ionallonglonge i yin heAshkenaziJewishpopula ionand
hei amilies ha e been s udied o de e mine ac o s ha could be
associa ed wi h his ai . Se e al epo s ha e indica ed ha he o -
sp ingo AshkenaziJewishcen ena iansha ehighe TSHle els han
he o sp ing o non-cen ena ians and, e en nonagena ians and hei
o sp ing, ha e inc eased TSH le els and/o dec eased ci cula ing
T3/ eeT4le els han hei pa ne s(A zmone al.,2009;Jansen,
e al., 2015). The Leiden longe i y s udy has also suppo ed he
associa ion be ween low hy oid unc ion wi h lowe isk o dea h
omca dio ascula diseaseandlonge li espans(Rozinge al.,2010;
Rozinge al.,2010;Wes endo pe al.,2009).In hisline,nonagena -
ians wi h he lowes amily mo ali y his o y sco e had he highes
TSHle elsandsligh lylowe le elso eeT4and eeT3(Rozing
e al., 2010). In e es ingly, TSH le els we e ound o be highe and
ee T3 le els we e sligh ly lowe when he o sp ing was compa ed
o hei pa ne s(Rozinge al.,2010).TheLeidenlonge i ys udy
also analyzed nonagena ians wi h a leas one nonagena ian sib-
ling, hei o sp ing, and hei pa ne s (Wes endo p e al., 2009).
Rema kably, au ho s de e mined ha o sp ings o nonagena ian
siblings had lowe mo ali y a e, and lowe p opensi y o de elop
ca dio ascula disease and DM han hei pa ne s. These obse a-
ions ha e led o he conclusion ha inc eased TSH le els a e associ-
a ed wi h excep ional longe i y, which has been u he suppo ed
by s udies in he oldes indi iduals o he gene al popula ion dem-
ons a ing he associa ion o highe TSH le els wi h educed old age
mo ali y(A zmone al.,2009;Gusseklooe al.,2004).Anelegan
wo kbyJansene al.hasde e minedTHle elsandTSHsec e ion
o e 24 hou s in he o sp ing om long-li ed amilies and hei pa -
ne s, since hese ho mones a e known o ha e in a-day oscilla ions
due o ci cadian hy hms. The objec i e was o e alua e al e a ions
in ene gy me abolism. Resul s ob ained led o he conclusion ha
amiliallonge i yischa ac e izedbyhighe TSHsec e ion,in heab-
senceo al e a ionsonTHle elso ene gyme abolism(Jansene al.,
2015). The lack o di e ences in TH le els and ene gy me abolism
is in sha p con as wi h se e al heo ies o aging pos ula ing ha
educed ene gy me abolism p omo es longe li e expec ancy.
In e es ingly despi e he ac ha cen ena ians and hei o -
sp ing end o ha e lowe TH unc ion, he o sp ing o cen ena ians
has a signi ican ly lowe body mass index when compa ed o he no -
mal popula ion and educed isk o age- ela ed diseases, u he indi-
ca ing a gene ic componen o longe i y (Te y e al., 2003). Fu he
in es iga ionsin heAshkenaziJewishpopula ionha ealsode e -
mined ha a gene ic backg ound migh be esponsible o inc eased
li e span, since wo speci ic single nucleo ide polymo phisms in he
TSHRgene( s12050077and s10149689)we elinked ohighe TSH
le els in cen ena ians and he o sp ing o cen ena ians o his pop-
ula ion(A zmone al.,2009).Basedon heLeidens udyando he s,
one can assume ha in he gene al popula ion o he oldes old, high
le els o TSH usually a e associa ed wi h heal hy aging (Gussekloo
e al., 2004). The ac ha TSH le els and no only TH le els a e
associa ed wi h ex ended su i al sugges s ha modula ions in he
nega i e eedback loop con olling TH p oduc ion migh con ibu e
o hispheno ype(A zmone al.,2009).
1.3 | The molecula mechanisms o
excep ional longe i y
An in ense a ea o esea ch has been ocused o iden i y he gene ic
p edisposi ion o maximal longe i y in animal models. Mu a ions in
he DAF2 gene, homolog o he insulin-like g ow h ac o 1 ecep-
o (IGF-1R) in Caeno habdi is elegans and in he IGF-1R in D osophila
melanogas e , a e known o ex end li e span (A an es-Oli ei a e al.,
2003; Ta a e al., 2001). Rema kably, he longes li ing labo a o y
mice exhibi se e ely educed hy oid unc ion as obse ed in he
La on (g ow h ho mone ecep o knockou ), Ames (P op1-mu a ed),
and Snell (Pi 1-mu a ed) dwa mice (Table 1) (B own-Bo g 2007,
2009; B own-Bo g e al., 1996). These mu ine models show a
heal hy aging pheno ype ha includes, besides he es ic ion on
hy oid unc ion, he p ese a ion o neu ocogni i e and muscula
unc ion, lowe incidence o cance s, enhanced insulin esponsi e-
ness, and imp o ed glucose ole ance (B own-Bo g, 2009; B own-
Bo g e al., 1996; Ikeno e al., 2003; Wiesenbo n e al., 2014). A
a molecula le el, hese mice exhibi educed signaling h ough he
insulin and IGF-1 pa hways, which leads o es ic ed phospho yla-
ion o downs eam a ge s such as he se um/glucoco icoid- egu-
la ed kinase and AKT. Res ic ed ac i i y o hese kinases p omo es
he ansloca ion o FOXO ansc ip ion ac o s in o he nucleus,
whe e i modula es he ansc ip ion o genes ha p omo e lon-
ge i y(B own-Bo ge al.,1996;Russell&Kahn,2007).Howe e ,
hese bene icial e ec s on heal h span and/o li e span migh ely
speci ically on g ow h ho mone p oduc ion and/o sensi i i y. In
his con ex , we ecen ly de e mined he di ec e ec o TH modu-
la ion in heal h span and longe i y using he PAX8 knockou mu ine
model and wild- ype mice ea ed o no wi h T4 (Lopez-No iega
e al., 2019). PAX8 is he mas e ansc ip ional egula o o hy oid
o ganogenesis equi ed o TH p oduc ion (Mansou i e al., 1998).
Using hese mice, we de e mined he e ec s in heal h s a us and
li e expec ancy in mice su e ing se e e hypo hy oidism, mild hy-
po hy oidism, and se e e hype hy oidism compa ed wi h con ol
heal hy mice. T4- ea ed hype hy oid mice exhibi ed educed body
weigh , inc eased ood in ake, and sho li e expec ancy, indica ing
ha ele a ed TH le els esul in li e- h ea ening oxici y. No su -
p isingly, he comple e lack o TH p oduc ion esul ed in pe ina al
mo ali y(Lopez-No iegae al.,2019).Thedi ec modula iono TH
le elsusingPAX8he e ozygousknockou mice,whichsu e amild
hypo hy oidism due o a di ec de ec in he hy oid gland, while ex-
hibi ing no mal ci cula ing le els o α-GSU o pi ui a y ho mones in
adul hood, did no esul in imp o ed heal h span o longe li e span.
As opposed o o he expe imen al models o hypo hy oidism (Hine
e al.,2017;Umezue al.,2020),we ound ha hePAX8he e ozy-
gous mice ai h ully ecapi ula e he pheno ype o humans wi h hy-
po hy oidism, including insulin esis ance, inc eased whi e adipose
issue (WAT) mass, and inc eased iglyce ide con en in skele al
6 o 25
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GAUTHIER ET Al.
muscle and li e (Lopez-No iega e al., 2019). Simila o humans,
hese mice also exhibi educed basal me abolic a e and obesi y
whilemain ainingno malene gyin ake.Mo eo e ,PAX8he e ozy-
gous mice exhibi poo pe o mance in unc ional physical es s and
accumula ed oxida i e damage, indica ing ha e en mild al e a ions
on TH le els (mild hypo hy oidism) ha e p o ound e ec s in heal h
span. These esul s indica e ha low TH le els in excep ional long-
li ing dwa mice a e no esponsible pe se o longe i y bene i s.
Ou da a suppo he no ion ha humans wi h excep ional longe i y
mus ha e a speci ic gene ic and/o epigene ic signa u e equi ed o
achie e longe i y bene i s (Bowe s e al., 2013; Gesing e al., 2012;
Jansen,e al.,2015).Inaddi ion,ou da aalsoindica e ha adeli-
ca e con ol o TH le els and unc ion is equi ed o sus ain heal h
and su i al and ha in e en ions based on he modula ion o THs
should no be a ge ed o imp o e he quali y o li e o li e expec-
ancy in heal hy indi iduals.
1.4 | The e ec o nu i ional and p o-longe i y
in e en ions in hy oid unc ion
Se e al animals, including humans unde calo ie es ic ion, a a i-
e y o nu i ional in e en ions ha ex end heal h span and li espan,
ha e low T3 and/o high TSH le els in he blood (De And ade e al.,
2015; Fon ana e al., 2006; Mulle e al., 2015; Ra ussin e al., 2015).
Rema kably, a ecen epo e alua ing he e ec s o 4-week al e -
na e day as ing has clea ly demons a ed a educ ion in T3 le els
in indi iduals adhe ed o he in e en ion, which is accompanied by
imp o emen s in ma ke s o ca dio ascula heal h (S eko ic e al.,
2020). In his line, a calo ic es ic ion mime ic, es e a ol, ises
TSH le els and has p o ound e ec s in he hy oid gland, dec eas-
ing sodium-iodide sympo e (NIS) and hy oglobulin (TG) exp es-
sion(Giulianie al.,2017).Calo ie es ic ionp oducese ec sa all
compa men s o he HPT axis, as well as in TH a ge issues. In
pa icula , educed hypo halamic TRH exp ession, educed pi ui a y
TSHβ exp ession, educed exp ession o TG and sec e ion o T3 and
T4 in he hy oid gland, and educed hepa ic DIO1 exp ession ha e
been desc ibed upon di e en o ms o calo ic es ic ion (Boelen
e al., 2008; De And ade e al., 2015; Palkowska-Gozdzik e al.,
2017). Di e en nu i ional in e en ions a e also known o al e
TH le els. In his ega d, adul dogs consuming a low-ca bohyd a e
high-p o ein high- a die exhibi ed g ea e ci cula ing T4 le els han
dogs ed wi h a high-ca bohyd a e low-p o ein low- a die (Chio alo
e al., 2019). In e es ingly, Ca ew e al. e alua ed he e ec o indi-
idual essen ial amino acid es ic ion on plasma TH concen a ions
inchickens(Ca ewe al.,1997).Resul sindica ed ha changesinci -
cula ing le els o T3 unde p o ein de iciency may be a consequence
o selec ed amino acid de ici s, since only isoleucine de iciency e-
sul ed in an ele a ion in plasma T3, while es ic ions on o he es-
sen ial amino acids did no al e T3 le els when compa ed o con ol
ed chickens. Howe e , he molecula mechanisms p oducing hese
changes emain unknown.
1.5 | Thy oid ho mones in diabe es melli us
1.5.1 | The implica ions o hy oid ho mones in
glucose and lipid me abolism
As p e iously men ioned, THs enhance oxygen consump ion, induc-
ing heca abolismo all ypeso ene gysou ces(Johannsene al.,
2012; Weins ein e al., 1991). THs a e e icien modula o s o lipid
and glucose me abolism. In pa icula , THs educe ci cula ing iglyc-
e ides and choles e ol-con aining lipop o eins. THs s imula e he
exp ession o he S e ol esponse elemen -binding p o ein 2 (S ebp-
2) (Mullu e al., 2014). Inc eased le els o S ebp-2 con ibu e o
enhance LDL ecep o exp ession, which po en ia es hepa ic choles-
e ol up ake. Mo eo e , THs a e known o inc ease simul aneously
lipolysis and liponeogenesis. Ac ually, THs a e known o inc ease he
exp ession o ca ni ine palmi oyl ans e ase Iα (mi ochond ial a y
acid up ake) and he ace yl-coenzyme A ca boxylase (lipogenic)
(Mullu e al., 2014). A comp ehensi e analysis o hese p ocesses
has indica ed ha liponeogenesis is enhanced o main ain lipid le els
unde condi ions o high lipolysis (Oppenheime e al., 1991). Unde
hese ci cums ances, lipolysis is enhanced o p o ide subs a es o
he mogenesis. Ca bohyd a e me abolism is also in luenced by TH.
Gluconeogenesis and glycogenolysis a e known o be enhanced by
THs in a p ocess ha suppo s issues wi h uel o main ain hei
ene gy equi emen s. In his sense, hepa ic insulin esis ance in hy-
pe hy oid indi iduals has been shown o inc ease gluconeogenesis
and subsequen hepa ic glucose ou pu (Figu e 3) (Klie e ik e al.,
2008;Po enzae al.,2009).Inc eased a eso gluconeogenesisa e
suppo ed by inc eased Co y cycle ac i i y, which implica es mus-
cle issue in he p o ision o subs a es o hepa ic gluconeogenesis
(lac a e and ce ain amino acids such as alanine and glu amine). This
p ocess ep esen s a dynamic bu e o glucose ha allows i s use
by o he issues unde glucose equi emen s when needed. Wi hin
he li e , THs a e known o enhance he exp ession o he phos-
phoenolpy u a e ca boxykinase, he a e-limi ing s ep in gluconeo-
genesis, suppo ing a di ec ole o THs in he egula ion o hese
p ocesses (Pa k e al., 1999). S udies in mice exposed o T4 mim-
icking hype hy oidism ha e also indica ed ha insulin signaling is
ac i e in insulin- a ge issues e en unde as ing condi ions, due o
a de egula ed unc ion o he endoc ine panc eas (e.g., inc eased in-
sulinsec e ionandsubsequen le elsinci cula ion)(Lopez-No iega
e al.,2017).O e all,compellingda ain heli e a u eindica e ha
THs p oduce e ec s in se e al, i no all, issues in ol ed in glucose
and lipid homeos asis (Figu e 3).
1.5.2 | Al e a ions o hy oid ho mones in
diabe es melli us
The ela ionship be ween al e a ions on hy oid unc ion and he de-
elopmen o di e en ypes o DM has been he ocus o in ense e-
sea ch. The p e alence o hype hy oidism in subjec s su e ing DM
|
7 o 25GAUTHIER ET Al.
TABLE 1 Gene ical e a ionscausing hy oiddys unc ionassocia edwi haging,DM,o cance inmiceandhumans.ND:no de e mined
Gene Func ion Al e a ion
Pheno ype
Re e encesAging DM Cance
DIO2 TH ac i a ion/
inac i a ion
Homozygous
knockou mouse
ND Se e al
hallma ks o
T2DM
ND Ma sili e al. (2011)
SNPs in humans ND Se e al
hallma ks o
T2DM
ND Canani e al. (2005);
Do a e al. (2010);
Men uccia e al.
(2002)
DUOX2 TH p oduc ion SNPs in humans ND ND P edisposes o
hy oid cance
Bann e al. (2019)
TG TH anspo SNPs in humans ND ND Found in hy oid
cance
Hishinuma e al., 2005)
THRαTH signaling Homozygous
knockou mouse
ND P o ec ed om
hallma ks o
T2DM
ND Jo nay aze al.(2012)
T unca ions and SNPs
in cance issue in
humans
ND ND Found in se e al
ypes o
cance
Kim and Cheng
(1830); Lin e al.
(1999); Kamiya
e al. (2002);
Puzianowska-
Kuznickae al.
(2002); Chan and
P i alsky
(2006); Rosen
and P i alsky
(2011) McCabe
e al. (1999); Cheng
(2003)
THRβTH signaling T unca ions and SNPs
in cance issue in
humans
ND ND Found in se e al
ypes o
cance
Kim and Cheng
(1830); Lin e al.
(1999); Kamiya
e al. (2002);
Puzianowska-
Kuznickae al.
(2002); Chan and
P i alsky (2006);
Rosen and
P i alsky (2011);
Cheng (2003)
TSHR TSH signaling Homozygous
knockou mouse
P ema u e dea h Glucose
in ole ance
ND Abe e al. (2003); Yang
e al. (2019)
T unca ions and SNPs
in cance issue in
humans
ND ND Mu a ions ound
in HCC and
hy oid cance
Shih e al. (2018);
Russo e al. (1995);
Camacho e al.
(2000)
PAX8 Thy oid
de elopmen
and unc ion.
Homozygous
knockou mouse
P ema u e dea h No No Lopez-No iegae al.
(2019); Mansou i
e al. (1998)
He e ozygous
knockou mouse
Unheal hy aging;
no mal li e
span
Se e al
hallma ks o
T2DM
Li e cance Lopez-No iegae al.
(2019)
Human SNPs ND GDM P opensi y o HCC Ma in-Mon al o e al.
(2019); Ma e al.
(2017)
(Con inues)
8 o 25
|
GAUTHIER ET Al.
is g ea e han in non-diabe ic subjec s (Biondi e al., 2019), and a
na ionwide Danish s udy has de e mined ha pa ien s su e ing hy-
pe hy oidism ha e g ea e isk o de elop DM (B and e al., 2013).
Among adul pa ien s wi h T2DM, ~4.4% ha e o e hype hy oid-
ism and 2%–4% ha e subclinical hype hy oidism (Biondi e al.,
2019). In e es ingly, imp o ed diabe ic con ol in T2DM pa ien s
no malizes TSH le els in pa ien s wi h subclinical hype hy oid-
ism, sugges ing ha ea men s imp o ing T2DM migh con ibu e
ono malize hy oid unc ion(Celanie al.,1994).Howe e ,a e-
cen epo has indica ed ha non-diabe ic pa ien s diagnosed wi h
hype hy oidism ha e inc eased isk o de elop T2DM la e in li e,
sugges ing ha hy oid dys unc ion migh p ecede diabe ogenic
p ocesses (Chen e al., 2019). In his line, while hype hy oid pa-
ien s exhibi inc eased basal hepa ic glucose p oduc ion and in-
c eased as ing insulin le els when compa ed o heal hy indi iduals,
hype hy oid pa ien s ea ed wi h me himazole ende ed eu hy-
oid, exhibi ed signi ican ly educed le els on he same pa ame e s,
eaching he le els o he heal hy con ol g oup (Ca allo-Pe in e al.,
1988). An independen epo has also indica ed ha pa ien s wi h
o e o subclinical hype hy oidism exposed o a glucose ole ance
es ha e highe ci cula ing le els o glucose and insulin (Ma a ou
e al., 2010). Glucose in ole ance in hese pa ien s is due o po en i-
a ed hepa ic gluconeogenesis (Ma a ou e al., 2010). These e ec s
migh be ela ed o he con ol ha exe s THs in he exp ession o
genes in ol ed in glucose and lipid me abolism and sugges s ha
se e al physiological abe a ions a e common o hype hy oidism
and T2DM, which con ibu e o he loss o me abolic homeos asis.
Longi udinal s udies ha e also in es iga ed he associa ion o al e a-
ions in hy oid unc ion and he p e alence o DM and me abolic
synd ome in olde adul s (Heima e al., 2013; Wa ing, e al., 2012).
A baseline, indi iduals in he me abolic synd ome g oup exhibi ed
signi ican ly highe TSH alues han indi iduals no included in he
me abolic synd ome g oup. The au ho s indica ed ha inc eased
ci cula ing le els o TSH we e associa ed wi h g ea e p e alence
o me abolic synd ome, e en in pa icipan s wi hin he no mal
ange (Wa ing e al., 2012). Ano he longi udinal s udy pe o med
in Ams e dam also associa ed highe p e alence o me abolic syn-
d ome and obesi y wi h indi iduals exhibi ing highe ci cula ing
le els o TSH (Heima e al., 2013). Sepa a ed esea ch as also indi-
ca ed ha hypo hy oidism is associa ed wi h insulin esis ance and
dyslipidemia(Dimi iadise al.,2006;Gie ach&Junik,2015;Wang,
2013). Fu he e idence also indica es an inc eased isk o DM in
pa ien s wi h hypo hy oidism and a sys ema ic e iew epo ed he
inc eased p e alence o e en subclinical hypo hy oidism in pa ien s
wi h T2DM (G onich e al., 2015; Han e al., 2015). As opposed o
compelling esea ch indica ing he associa ion o DM and hy oid
dys unc ion, which is suppo ed by he well-desc ibed ole o THs
on glucose me abolism and insulin sec e ion, o he s udies ha e
ailed o link hypo hy oidism o he de elopmen o T2DM (Ishay
e al., 2009; Radaideh e al., 2004).
A g owing e idence is associa ing al e a ions in hy oid unc ion
wi h o he ypes o DM such as ype 1 DM (T1DM) and ges a ional
DM (GDM). Se e al s udies ha e shown ha pa ien s wi h T1DM,
an au oimmune disease, a e p one o exhibi au oimmune hy-
oiddiseasessuchasHashimo o's hy oidi isandG a es’disease.
Cu en da a indica e ha up o 30% o adul s wi h T1DM ha e hy-
oid diseases o au oimmune o igin (A aujo e al., 2008; Shun e al.,
2014). Gene ic s udies ha e e ealed suscep ibili y genes o his
synd ome, which include he human leukocy e an igen, cy o oxic
T-lymphocy e-associa ed an igen 4, p o ein y osine phospha ase
non- ecep o ype 22, o khead box P3, and he in e leukin-2 ecep-
o alpha/CD25gene egion(Di ma &Kahaly,2010).Thesegenes
a e in ol ed in immunological synapse and T-cell ac i a ion, sug-
ges ing ha simila pa hogenic p ocesses occu in T1DM and hy oid
diseaseso au oimmuneo igin(Di ma &Kahaly,2010).
Ges a ional DM is a common complica ion ha a ec s ~10% o
all p egnancies associa ed wi h ad e se p egnancy ou comes, such
as p eeclampsia, mac osomia, and caesa ean deli e y (In e na ional
Associa ion o Diabe es, 2010; Pe a e al., 2019). Upon deli e y,
GDM disappea s bu in many cases di e en ypes o DM (GDM
in a subsequen p egnancy o T2DM) can spu la e in li e (Ma in
e al.,1999;Seely&Solomon,2003).Among hechanges ha occu
du ing p egnancy, i is known ha he placen a inc eases he sec e-
ion o p o-in lamma o y cy okines ha induce insulin esis ance o
a o nu ien a ailabili y o he e us (Kim e al., 2010). Unde hese
ci cums ances (e.g., ansien insulin esis ance du ing p egnancy),
GDM is he esul o comp omised capaci y o panc ea ic β-cells o
inc ease insulin sec e ion o compensa e insulin esis ance in insu-
lin- a ge issues (Kuhl, 1991). Se e al epo s ha e de e mined ha
ma e nal hypo hy oidism p edisposes he o sp ing o exhibi limi ed
Gene Func ion Al e a ion
Pheno ype
Re e encesAging DM Cance
PIT-1 TRH/TSH
p oduc ion
Homozygousloss-
o - unc ion poin
mu a ion in mouse
Delayed aging Inc eased
insulin
sensi i i y
Reduced
occu ence o
spon aneous
cance
B own-Bo g(2007);
Flu key e al.
(2001); Alde man
e al. (2009)
PROP-1 TRH/TSH
p oduc ion
Homozygousloss-
o - unc ion poin
mu a ion in mouse
Delayed aging Inc eased
insulin
sensi i i y
Delayed
spon aneous
occu ence o
cance
B own-Bo g(2007)
B own-Bo g e al.
(1996); Ikeno e al.
(2003)
TABLE1 (Con inued)
|
9 o 25GAUTHIER ET Al.
insulin sec e ion and o de elop glucose in ole ance, inc easing he
isk o T2DM in he o sp ing (Ka balaei e al., 2013). Mo eo e , sep-
a a ed epo s ha e also de e mined ha hypo hy oidism is associ-
a ed wi h GDM (Ma in-Mon al o e al., 2019; Sell e al., 2008). In
his ega d, we ound se e al mu a ions in PAX8 leading o hypo hy-
oidism associa ed wi h he de elopmen o GDM, indica ing ha
human GDM could ha e a gene ic componen (Ma in-Mon al o
e al., 2019). Rema kably, his wo k has e ealed ha PAX8 exp es-
sion in panc ea ic isle s modula es cellula pa hways in ol ed in cel-
lula su i al (Ma in-Mon al o e al., 2019).
1.5.3 | The physiological and pa hophysiological
ole o hy oid ho mones in he endoc ine panc eas
One o he main o gans in ol ed in he con ol o ci cula ing glucose
le els is he endoc ine panc eas. Ex ensi e esea ch has demon-
s a ed he ole o THs in he di e en ia ion, ma u a ion, and unc-
ionali yo me abolic issues(Figu e3)(Mas acci&E ans-Molina,
2014). In i o esea ch has de e mined ha du ing pos na al de el-
opmen ci cula ing le els o T3 inc ease and induce he exp ession o
he MAF bZIP ansc ip ion ac o A (MAFA) and THRs in panc ea ic
FIGURE 3 Schemesumma izing hep ocesses egula edbyTHsin hemainme abolic issues.THsexe p o ounde ec sinme abolic
issues. THs enhance GK and MAFA exp ession in he panc eas a o ing a apid ma u a ion and u no e o β cells. THs also po en ia e
insulin exp ession and sec e ion in he endoc ine panc eas. Insulin- a ge issues espond inc easing he ac i i y o insulin signaling, which
p oduces inc eased a es o lipolysis and gluconeogenesis in he li e and p o eolysis and mi ochond ial biogenesis in he skele al muscle.
Adipose issues espond oTHsinc easinglipolysisandlipidmobiliza ion.B owning/beigingo adipocy esoccu sin heWATandinc easing
he mogenesis ia inc eased UCP exp ession and subsequen lipolysis occu s in he BAT. AKT, p o ein kinase B. FOXO: o khead box O 1.
GK: glucokinase. GLUT4: glucose anspo e 4. MAFA: MAF bZIP ansc ip ion ac o A
16 o 25
|
GAUTHIER ET Al.
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