Thyroid Hormone Signaling and Homeostasis During Aging

R E V I E W
Thyroid Hormone Signaling and Homeostasis

During Aging
J. Bowers,* J. Terrien,* M. S. Clerget-Froidevaux, J. D. Gothie, M. P. Rozing,

R. G. J. Westendorp, D. van Heemst, and B. A. Demeneix
Centre National de la Recherche Scientifique (J.B., J.T., M.S.C.-F., J.D.G., B.D.), Unite Mixte de Recherche 7221,
Evolution des Regulations Endocriniennes, Departement Regulations, Developpement et Diversite Moleculaire,
Museum National dHistoire Naturelle, 75231 Paris Cedex 5, France; and Department of Gerontology and Geriatrics
and Netherlands Consortium of Healthy Aging (M.P.R., R.G.J.W., D.v.H.), Leiden University Medical Center, 2300 RC
Leiden, The Netherlands
Studies in humans and in animal models show negative correlations between thyroid hormone (TH) levels and
longevity. TH signaling is implicated in maintaining and integrating metabolic homeostasis at multiple levels,
notably centrally in the hypothalamus but also in peripheral tissues. The question is thus raised of how TH
signaling is modulated during aging in different tissues. Classically, TH actions on mitochondria and heat
production are obvious candidates to link negative effects of TH to aging. Mitochondrial effects of excess TH
include reactive oxygen species and DNA damage, 2 factors often considered as aging accelerators. Inversely,
caloric restriction, which can retard aging from nematodes to primates, causes a rapid reduction of circulating
TH, reducing metabolism in birds and mammals. However, many other factors could link TH to aging, and it is
these potentially subtler and less explored areas that are highlighted here. For example, effects of TH on
membrane composition, inflammatory responses, stem cell renewal and synchronization of physiological re-
sponses to light could each contribute to TH regulation of maintenance of homeostasis during aging. We
propose the hypothesis that constraints on TH signaling at certain life stages, notably during maturity, are
advantageous for optimal aging. (Endocrine Reviews 34: 556 589, 2013)
I. Introduction IV. Metabolic/Molecular Targets of Thyroid Signaling

A. Thyroid hormones in an evolutionary perspective Linked to the Aging Process
of longevity A. Mitochondrial activity
B. Animal models for slow aging: the long-lived Ames B. Activation/silencing of the JNK pathway
and Snell dwarf mice C. Role of N-acylethanolamines and endocan-
II. Longevity Is Associated With Decreased Thyroid Hor- nabinoids
mone Signaling in Animal Models D. Selenium, TH signaling, and aging
A. Age-dependent correlation between thyroxine lev- E. Aging-associated genes and TH signaling
els and longevity V. Clinical Data Linking TH to Longevity
B. Gender modulates the effects of TH signaling on A. Experimental data in humans confirm the existence
longevity of TH/longevity cross talk
III. TH Signaling and Homeostatic Maintenance in B. Human population studies: TH and longevity
Longevity C. Rejuvenating strategies in humans
A. The hypothalamus VI. TH Signaling and Key Biological Aging-Linked
B. The sympathetic nervous system Processes
C. Inflammation and the immune response in the con- VII. Concluding Remarks
text of homeostatic maintenance during aging
D. Growth pathways and insulin signaling * J.B. and J.T. contributed equally to this work.
E. Synchronization to light-dark cycles Abbreviations: 2-AG, 2-arachidonoyl glycerol; AITD, autoimmune thyroid disease;
F. Hormesis, caloric restriction, and mimetics AMPK, AMP-activated protein kinase; BAT, brown adipose tissue; CNS, central
nervous system; CR, caloric restriction; CRP, C-reactive protein; D1, -2, -3, deiodinase
G. Thyroid hormones, stem cell renewal, and tissue types 1, 2, 3; Dio1, -2, -3, deiodinase-encoding genes; fT3, free T3; fT4, free T4; GC,
regeneration glucocorticoid; HFD, high-fat diet; HPT, hypothalamus-pituitary-thyroid; JNK, c-Jun
N-terminal kinase; KO, knockout; LD, light-dark; mTOR, mammalian target
ISSN Print 0163-769X ISSN Online 1945-7189 of rapamycin; NAE, N-acylethanolamine; PGC-1, PPAR coactivator-1 ; PPAR, per-
Printed in U.S.A. oxisome proliferator-activated receptor; ROS, reactive oxygen species; Sirt1, Sirtuin 1;
Copyright 2013 by The Endocrine Society SNS, sympathetic nervous system; T2, diiodothyronine; T2DM, type 2 diabetes mellitus;
Received August 31, 2012. Accepted February 22, 2013. T3, triiodothyronine; T4, thyroxine; TH, thyroid hormone; THR, TH receptor; TLR, toll-
First Published Online May 21, 2013 like receptor; UCP, uncoupling protein.
556 edrv.endojournals.org Endocrine Reviews, August 2013, 34(4):556 589 doi: 10.1210/er.2012-1056
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 06 July 2016. at 00:06 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/er.2012-1056 edrv.endojournals.org 557
I. Introduction and maturation (13, 14). It is noteworthy that the timing

and the amplitude of this peak might have a major role in
he escalating economic burden of age-related diseases
T accentuates the urgency of grasping the complexity
of the aging process, as well as understanding individual
the settlement of the life-history trade-off between growth,
metabolism, and inflammation axes, which is required for
homeostasis maintenance (Figure 1B). After reproduction,
differences in aging trajectories (1). Several key factors evolutionary pressure slackens and for a significant num-
affecting aging rates in mammals have been identified (2), ber of living organisms, such as insects, postreproductive
including classical endocrine signals such as insulin, GH, life span can be very short, particularly in situations where
IGF-I, and thyroid hormones (THs). Each of these metab- offspring compete with parents. However, this gap will be
olism-controlling signals determines an organisms capac- greater in animals where a positive influence on the sur-
ity to adapt to changing environments (3). Moreover, vival of species offspring is achieved by social interactions
these 4 signaling pathways are intimately linked, exerting and parental care, especially in humans, although such
many reciprocal controls (4) and making it difficult to explanations remain controversial (15). Thus, the late
consider 1 pathway independently of the others. Here we pathophysiological phase of life, aging, is free of strong
focus on the hypothalamus-pituitary-thyroid (HPT) axis evolutionary pressure (16). Aging can be defined as the
and potential mechanisms linking TH to aging. It should functional deterioration of the organism due to a stochas-
be noted that our aim is not to address specific diseases that tic process of accumulative molecular and cellular damage
occur at increased frequency during aging or that are se- resulting in increased probability of disease and ultimately
verely exacerbated by altered TH signaling, such as os- death. These processes, of which the rate (namely rate of
teoporosis and heart failure, but rather to focus on TH aging) determines longevity, largely occur during the pe-
links to general cellular and molecular metabolic controls riod of life following reproduction (including parental
in the central nervous system (CNS) and the periphery that care). It is assumed that aging is characterized by the al-
in turn could influence the rate of aging. teration of hormonal signaling, among which are declin-
ing TH levels (Figure 1A), as reflected for example by the
A. Thyroid hormones in an evolutionary perspective of age-associated disruption in circadian rhythmicity result-
longevity ing in the deterioration of hormonal secretory patterns
Understanding aging, like most biological problems, is (17). In an evolutionary perspective, the second phase of
aided, as Dobzhansky so famously underlined (5), by in- life can be heavily influenced by the earlier processes es-
cluding an evolutionary perspective (Figure 1A). Selection tablished to support successful reproduction. Following
drives optimization of developmental processes and phys- this line of argument and in accordance with the theory of
iological responses to environmental stress, in particular antagonistic pleiotropy (18), it is feasible that long-lived
reproduction, during the first phase of life (Figure 1A). aged individuals profit from less efficient optimization of
Owing to the decline of the force of natural selection with the first phase of life (Figure 1A, scenario 2). In these less-
postreproductive age, there is little selection against late- optimized individuals, survival during the second phase
life negative consequences of this optimization process. of life will be characterized by a lower rate of aging and a
This assumption conforms to the disposable soma theory, lesser negative influence on aging that might result from
which proposes a trade-off between the associated costs of the optimal characteristics generally required in the first
reproduction and germinal success, vs longevity (longevity phase. This chance survival would then be accompa-
being the result of enhanced investment in somatic main- nied by a decreased prevalence of disease and, thus, in-
tenance and repair) (6, 7). Although this theory is still creased longevity. Some species-specific examples would
debated (8, 9), much evidence suggests that exceptional include naked mole rats, which live up to 30 years of age
longevity is linked to decreased investment in reproduc- and survive in a colonial habitat containing only 1 breed-
tion (6, 10, 11). Levels of circulating hormones triiodo- ing female (19); and Dwarf mice, which struggle with a
thyronine (T3) and thyroxine (T4) generally increase dur- fragile phenotype yet under laboratory conditions are ca-
ing development, establishing the physiological and pable of surviving more than 50% longer than ordinary
behavioral parameters required to efficiently tackle the mouse strains (20). We propose the hypothesis that TH
challenge of reproduction. Of particular interest are the signaling might play a major role in this trade-off and
dramatic perinatal and postnatal hormonal changes oc- deeply influence aging rates (Figure 1B).
curring in mammals (12) that characterize independent B. Animal models for slow aging: the long-lived Ames
homeostatic regulation after separation from the placenta. and Snell dwarf mice
TH levels follow the same trend, peaking before dropping Several mouse models show that endocrine and meta-
to a plateau (Figure 1A), thus contributing to development bolic signals interact with aging pathways. Much evidence
558 Bowers et al TH Signaling and Homeostasis During Aging Endocrine Reviews, August 2013, 34(4):556 589
Figure 1.
Figure 1. Evolutionary perspectives on the role of TH signaling on functional optimization and longevity. This figure schematizes how variations in
TH signaling may modulate early life events and thereby affect aging patterns. The respective advantages of 2 distinct patterns of maturation and
development are compared (A). The first phase of life is characterized by optimization of equilibrium between the environment and physiology to
favor germinal maturity, reproduction, and parental care. Of particular interest is the dramatic increase of TH signaling in the very early stages of
life, orchestrating development and maturation (A). Following reproduction, evolutionary pressure lessens, and the organism enters a state
characterized by the somatic repair, thereby limiting the damaging effects of chronological age. This phase is characterized by a general decrease
in endocrine signals, including TH levels. The trade-off operated between the requirements of the rising physiological phase and the declining
pathophysiological phase preconditions the aging process and longevity (B). In scenario 1 (red), the maturation and developmental patterns
optimize fitness. However, this scenario does not ensure optimization of somatic repair and survival. In contrast, scenario 2 (green) is characterized
by lower efficiency of physiological properties during development/maturation (eg, caused by mutations or by harsher environmental conditions).
Scenario 1 provides greater advantage in development/reproduction, but those less advantageous physiological characteristics of scenario 2
could be beneficial for tissue repair and survival later on and could thus improve health span. Such a trade-off is an example of antagonistic
pleiotropy (B).
comes from 2 spontaneous mutant mouse models, the eterious and thus counterselected in wild conditions
Ames and Snell dwarf mice, that have each reduced activ- because the phenotype could be described as markedly
ity of the somatotrophic, lactotrophic, and thyroid axes. more fragile and thus more susceptible to being lost
Both strains exhibit a consistent increase in life span of at through selection. However, maintenance in captive con-
least 40%, which can be extended to 70% as a function of ditions permits early-life survival resulting in an excep-
gender, diet, and housing conditions of individual mice tional postreproductive phenotype, notably characterized
(21). Dwarfism results from mutations in transcription by extended longevity. Although it is generally accepted
factor-encoding genes (directly altering GH, prolactin, that decreased GH or IGF-I signaling is associated with an
and TSH signaling) expressed in the anterior pituitary increased life span (20, 21), the specific gene/environment
gland in Ames mice, Pit-1, and during anterior pituitary interactions involved in the dwarf mouse models are not
development in Snell mice, Prop-1 (22). Other pathway successfully optimized for the first phase of life. This lack
perturbations have also been recorded, including in- of optimization results in low reproduction capacity and
creased insulin sensitivity (23). From an evolutionary per- altered homeostatic control in these mice, notably char-
spective, these spontaneous mutations would likely be del- acterized by decreased thermoregulatory capacities and
greater whole-body metabolism (24). In contrast, the product is the prohormone T4. Although TH available to
physiological characteristics of dwarfism (eg, increased tissues derives from the circulation, intracellular T3 ho-
hepatic sensitivity to insulin, reduced fasting plasma glu- meostasis determines TH responses in tissues (32, 33).
cose, reduced generation of reactive oxygen species [ROS], Cell-specific availability of TH (Figure 3) is governed by
improved antioxidant defenses, increased resistance to ox- combinations of controls and receptors found at the levels
idative stress, and reduced oxidative damage) appear to of the cell membrane (TH transporters, deiodinase D3,
be extremely beneficial for protecting tissues from po- integrin 3), the cytoplasm (deiodinases D1 and D2),
tential damage, thus delaying the aging process (Figure and in the nucleus (TH receptors [THRs]). D2 is an acti-
1, scenario 2). In particular, dwarf mice demonstrate vating enzyme because it carries out outer-ring deiodina-
high resistance to stress through implication of several tion of T4, forming the biologically active T3. T4 is con-
metabolically induced genetic factors, such as Sirt1, verted to an inactive metabolite, rT3, by the inactivating
Foxo, Klotho, and P66shc (25, 26). enzyme D3. D3 also inactivates TH by converting T3 to
Although the importance of the GH/IGF-I axes in these diiodothyronine (T2). Although Dio2 and Dio3 are tran-
mice has received much attention, the contribution of thy- scriptionally regulated, in particular by T3 in cellular mod-
roid signaling in the long-lived dwarf phenotype is much els (34), the transcriptional control of these enzymes is not
less studied. Nevertheless, a critical role of TH has been as marked as that of Dio1. Additionally, D2 can be reg-
clearly established in Snell mice, where combined reduced ulated post-transcriptionally by T4 (35). Dio3 is an im-
TH and IGF-I signaling results in the long-lived phenotype printed gene in mammals (36, 37). Dio1, encoding D1, is
(27). Indeed, 11 weeks of coupled T4 and GH injections, mainly expressed in liver, kidney, pituitary, and thyroid
inducing hyperthyroidism and increased IGF-I levels, re- (38). In humans, no D1 is expressed in the CNS, whereas
spectively, reversed the dwarf phenotype with positive ef- in other vertebrates D1 expression is found in certain brain
fects on body mass and sexual maturation but had no regions (38). The principle substrates of D1 are T4 and
effect on life span. Strikingly, lifelong supplementation of sulfated iodothyronines. In the liver and other peripheral
T4, ie, maintenance of hyperthyroidism for a longer pe- tissues, D1 converts T4 to T3, contributing to circulating
riod, in mice that had received coupled T4/GH injections T3. D1 also plays a significant role in the degradation of
resulted in diminished survival (27), strongly supporting rT3 to T2 (38 41). Other metabolites of THs include thy-
the hypothesis of a critical role of TH in the long-living ronamines such as 3-iodothyronamine that are known
phenotype of dwarf mice. Following this line of argument, to induce hypothermia and decrease metabolic rate
it is interesting to note that specific alterations of the GH/ through interactions with the CNS (42). Additionally,
IGF-I axis alone do not extend life span to the same extent studies of the TH metabolite 3,5- diiodo-L-thyronine
in the dwarf mouse models of mixed alterations in TH and (3,5-T2) suggest mitochondria- specific effects of some
IGF-I signaling (28, 29). Correlative analysis of TH, GH, TH products (43).
and IGF-I is, however, quite complicated due to sex dif-
ferences in hormonal patterns and the effects of altered A. Age-dependent correlation between thyroxine levels
and longevity
GH pulsatile secretion on the rodent liver (30). Finally, in
relation to other models, including humans, study of La- Data from in vivo studies on a number of small mam-
ron syndrome resulting from IGF-I deficiency has pro- malian species show that reduced TH levels are associated
vided some parallels between mice with disruption of GH with extended longevity. A comprehensive review by
axis and other species, suggesting that similar mechanisms Buffenstein and Pinto (44) highlighted the negative cor-
may be at play (31). relation that exists between T4 levels and maximum spe-
cies life span in 4 small mammals: mice, guinea pigs, Da-
mara mole rats, and naked mole rats. The naked mole rat
has strikingly low T4 levels and a long life span (19). We
II. Longevity Is Associated With Decreased
Thyroid Hormone Signaling in Animal Models expanded this analysis with an original set of data assess-
ing the correlation between T4 and life span in a range of
Before discussing TH signaling and its role in the rate of mammals of varying sizes and habitats (Figure 4). Nega-
aging, the key elements implicated in controlling its pro- tive correlations between total T4 and species life span for
duction can be succinctly recalled. TRH, synthesized in the the 2 groups of animal species studied were observed, con-
paraventricular nucleus of the hypothalamus, regulates curring with Buffenstein and Pinto (44).
the synthesis and release of TSH from the anterior pitu- Some rodent studies on aging have focused specifically
itary (Figure 2). In turn, TSH stimulates the thyroid gland on TH signaling. For instance, one of the first reports in
to produce and secrete TH. The main thyroid secretory this area described increased longevity in hypothyroid and
Figure 2. of TH changes over life span, with a

general trend to decreasing TH levels
with age. We evaluated correlations
between the median life span re-
corded in the Yuan2 dataset (46) and
mean serum T4 levels observed in
males from different strains, mea-
sured at 4, 6, 12, and 18 months (Fig-
ure 5). To avoid disease bias, we used
datasets where disease models or dis-
ease susceptibility model data were
removed. This original set of data
showed that T4 levels were nega-
tively correlated with median life
span of mouse strains in young adult
male mice. Although this correlation
was maintained at 6 months of age
(Figure 5A), it tended to invert at 12
months (Figure 5B) and was lost at
18 months. We then examined cor-
relations between changes in T4 lev-
els (6 vs 18 mo) and median life span
(Figure 5C). A negative correlation
between life span and amplitude of
changes in T4 levels was found. To-
gether, these findings suggest that
low T4 signaling in young adults and
limited changes between young and
old adult ages are associated with ex-
tended life span in male mice. What
happens in maturity is a matter of
stochasticity resulting in the occur-
rence of age-related damage and dis-
ease, which TH signaling could af-
Figure 2. Simplified overview of the HPT axis. Stimulation of the hypothalamus results in TRH fect. However, it appears quite clear
release, which increases TSH secretion from the pituitary. TSH acts to increase TH production and that these 2 phenomena, ie, the early-
secretion from the thyroid gland. Hypothalamic signals can also directly influence peripheral
stage and the late-stage effects of TH
tissues via the SNS. THs are secreted into the circulation, and they enter target tissues such as
liver, BAT, and white adipose tissue (WAT). The main form released into the blood is T4, which in on development/growth and longev-
turn can be locally activated into T3 by deiodinases D1 and 2. Pathways of TH deactivation ity, respectively, contribute sepa-
(involving deiodinase D3) are not included in this simplified schematic view of the HPT axis, rately to affect the rate of aging.
although their roles are of particular importance in the brain for example.
We used the same strategy to ex-
amine correlations of IGF-I levels
decreased longevity in hyperthyroid Wistar rats, as com- with longevity. IGF-I is a key player in aging, and de-
pared with euthyroid controls (45). We revisited this ques- creased IGF-I signaling is associated with extended life
tion using the Jackson Mouse Phenome Database (http:// span in a range of model organisms, including rodents
phenome.jax.org/) to test for associations between (23). It is possible that the influence of TH on aging in-
longevity of males from different mouse strains and serum volves interactions between TH and IGF-I signaling path-
total T4 levels at different ages. No data were available for ways because the 2 pathways are intimately connected (see
free T4 (fT4), T3, or TSH. Section III.D). Yuan et al (46) showed that IGF-I concen-
A first observation was the significant variability in lev- trations, measured at different ages and in different indi-
els of circulating TH between mouse strains. There were vidual mice, were correlated with life span. We reanalyzed
also marked differences between strains in the magnitude these data using data from the same strains as for T4 levels
Figure 3.
Figure 3. Schematic representation of cellular availability and turnover of THs. Cell-specific availability of TH is governed by combinations of
controls and receptors found at the levels of the cell membrane (notably TH transporters [THT]), cytoplasm (deiodinases D1 and D2), and in the
nucleus (THRs). After release to the peripheral circulation by the thyroid gland, T4 and T3 enter the cells by THTs and undergo a number of
modifications under the control of deiodinases activity in a tissue-specific manner. D2 is an activating enzyme because it carries out outer-ring
deiodination of T4, forming the biologically active T3, which then binds to the THRs and activates transcription. T4 can also be converted to an
inactive metabolite, rT3, by the inactivating enzyme D3. D3 also inactivates TH by converting T3 to T2. The activating and inactivating enzyme D1 is
not expressed in all brain regions but acts as an inactivating enzyme in the periphery, notably in metabolic tissues such as the liver.
and found that IGF-I levels were only correlated with me- the associations were not significant at 12 months. The ob-
dian life span at 6 months in males (Figure 5D), confirming served patterns of correlations between T4 and IGF-I levels
the hypothesis of an inherited developmental trait. Al- with median life span at young stages of life in males (4 6
though correlations in older mice followed the same trend, mo) can be related to the tight links between TH and IGF-I
signaling (4). However, in later life (12
Figure 4. mo), the trends between longevity and
either T4 or IGF-I levels are inverted
(although significant correlations are
lost; Figure 5), suggesting differential
roles of TH and IGF-I signaling on
aging. Such differences are con-
firmed when considering age-depen-
dent changes in hormone levels
(Figure 5, C and F) because no cor-
relation between changes in IGF-I
and median life span could be ob-
served, whereas such a link was
found for TH (Figure 5, C vs F). Such
a dichotomy in the correlations be-
Figure 4. Spearman correlations between total circulating T4 (tT4 in g/dL) and median life span tween T4/life span and IGF-I/life
in a range of mammalian species of different sizes. A, Small mammals maintained under span confirms that despite concom-
domestic or laboratory conditions weighing between 0.025 and 30 kg (n 6); data included itant influences on the rate of aging,
guinea pig, naked mole rat, mouse, ferret, dog, and cat. B, Large wild animals (n 11); data
were taken from mammals with access to a wild-type environment weighing between 3 and 350 T4 and IGF-I might be differentially
kg. Data included jaguar, puma, ocelot, jaguarundis, margay, lion, elephant seal, llama, sheep, responsive to and differentially af-
bottlenose dolphin, and donkey. All tT4 data used were taken from young adults under regular fect the state of aging, suggesting dis-
diet for that species. Distinction of size and habitat was made in order to avoid any confounding
effects of these 2 parameters on T4 levels and longevity. These correlations represent an original
tinct roles for T4 and IGF-I signaling
set of data that has never been published before. on aging patterns and longevity.
Figure 5.
Figure 5. Age-associated correlations between total circulating T4 (tT4 in g/dL) and IGF-I (in ng/mL) levels and median life span. Spearman correlations
were tested between total (A and B) or changes (C) in T4 serum levels, total (D and E) or changes (F) in IGF-I levels, and median life span in different
strains of mice at different ages (data collected from the Yuan2 study available at http://phenome.jax.org/). A and B, Correlations were tested on male
mice at 6 months (A, n 10) and 12 months (B, n 12). C, Also plotted are changes in total T4 between 6 and 18 months against the median life span
of the same mice strains (n 11). All correlations were tested, but significance was reached only when plotting change in T4 between 18 and 6 months
against life span. D and E, Correlations were tested on male mice at 6 months (D, n 12) and 12 months (E, n 11). F, Also plotted are changes in IGF-I
between 6 and 18 months against the median life span in the same mice strains (n 12). All correlations were tested, and none were significant. Median
life span is defined as the age at which half of the population was deceased. The number of mice strains included in the correlation analyses differed
according to data availability. IGF-I and T4 assays were carried out on samples taken from different individual mice and using protocols adapted to mouse
models. These correlations represent an original set of data that has never been published before.
B. Gender modulates the effects of TH signaling TH signaling and sex steroids, in particular estrogens, at
on longevity the molecular, cellular, and physiological levels (50, 51).
The sections on cellular and molecular mechanisms Such interactions between TH signaling and estrogens
that follow will not include discussion of gender-specific could lead to differential patterns of somatic aging be-
effects. However, it is evident that differences between tween males and females. For example, considering me-
males and females are expected with regard to age-asso- tabolism in brown adipose tissue (BAT), aged female mice
ciated changes in TH signaling and regulation of homeo- showed improved capacities for resisting cold challenges
stasis. The interactions of IGF-I and TH on aging are compared to males (52). Furthermore, a strong positive
somewhat gender-dependent. With regard to our data correlation between T3 levels and BAT parameters was
analysis, Spearman correlations between T4 or IGF-I and observed in females only, suggesting a potential role for
median life span in females were carried out (data not TH in the establishment of age-related sexual dimorphism
shown). In females, despite the lack of statistical signifi- in the maintenance of thermogenic homeostasis in mice.
cance, T4 correlations followed the same trend as in male
mice. As to IGF-I, a correlation between IGF-I and median
life span was found in females at 6 months and persisted
III. TH Signaling and Homeostatic Maintenance
until later in life than in males, still being evident at 12 in Longevity
months (data not shown).
Many species have differential rates of aging and dif- The following sections address the roles of TH signaling
ferent aging-related disease patterns in females and males in the regulation of homeostasis during aging. A number
(47 49). Moreover, multiple interactions exist between of homeostatic regulators that affect cellular and mo-
Figure 6.
Figure 6. Schematic representation of integrated, age-related influences in the HPT axis activity. Stimulation of the hypothalamus results in TRH
release, which increases TSH release from the pituitary. TSH acts to increase TH production and secretion from the thyroid gland. Hypothalamic
signals can also directly influence peripheral tissues via the SNS. Low circulating TH levels are associated with longer life span. THs are secreted into
the circulation, and they enter target tissues such as liver, BAT, and white adipose tissue (WAT), where they are locally activated by deiodinases D1
and D2 and deactivated by deiodinase D3. Deiodinases contain selenium, higher levels of which are associated with decreased aging-associated
disease prevalence in adults. The influence of aging on the HPT axis is more profound in peripheral tissues than in the hypothalamus. Metabolic
parameters (nutritional status, diet composition, etc), environmental conditions (food availability, ambient temperature), and immune stimuli will
affect NAEs, JNK, and UCP1 activities as well as membrane saturation and then modulate the HPT axis in an integrative manner. The presence of
NAEs influences pituitary activity, whereas JNK influences both the hypothalamus and the pituitary gland. Integration of photic and metabolic
stimuli (such as insulin, GH/IGF-I) and their age-associated alterations occur at a central level and will therefore influence the functioning of the
HPT axis. PUFAs, polyunsaturated fatty acids.
lecular targets at the central and/or peripheral level ity. Many of these regulatory responses are controlled in
linked to senescence and longevity have been identified, the hypothalamus. Aging can impair homeostatic main-
and are potentially under the influence of TH signaling. tenance and alter cognitive function (53), thus resulting in
Figure 6 presents a simplified view of potential inter- greater frailty toward environmental changes. However,
actions between the HPT axis and targets discussed there might exist a threshold at which physiological dete-
herein: the hypothalamus, the sympathetic nervous sys- riorations lead to a switch from shortened to extended life
tem (SNS), inflammatory responses, growth, and pho- span. An abundant, but disparate, literature (54) suggests
toperiodic adaptation. that adjustability of hypothalamic set-points (and their
resetting) and/or key switches might be compromised in
A. The hypothalamus humans that undergo less optimal aging as opposed to
Evolutionary selection has optimized physiological and those who age with little or no evidence of poor health.
behavioral mechanisms maintaining homeostatic stabil- Not surprisingly, 2 primitive and highly essential hypo-
thalamic control systems seem to be most at risk during C. Inflammation and the immune response in the
aging, metabolic control and the stress axis. Metabolic context of homeostatic maintenance during aging
disorders and associated cardiovascular/skeletomuscular Cross talk between TH homeostasis and the immune
bone diseases rank among the most frequent complaints in system is extensive because both processes act to restabi-
aged individuals. Such reports highlight age-related per- lize the internal environment in response to external
turbations in the regulation of energy metabolism (55), challenge.
with perturbations in insulin, glucocorticoid (GC), and
1. Inflammation, TH homeostasis, and aging
TH signaling. As for the stress axis, there is evidence that
It is well established that a high-fat diet (HFD), result-
older subjects may react more strongly (and for a longer
ing in diet-induced obesity, increases proinflammatory
period) to stress, resulting in hypersecretion of GCs, hor- signaling in the hypothalamus (68 71), thus altering in-
mones that have a major impact not only on metabolism sulin signaling. This response involves the action of c-Jun
but also on cognition and mood through their ability to N-terminal kinase (JNK) and nuclear factor-B. As well,
affect neuroplasticity (neuronal survival, morphology, type 2 diabetes mellitus (T2DM) is associated with in-
biochemistry, and electrophysiology) in the brain (56). creased inflammatory markers such as TNF, originating
in adipose tissue, which can also activate the JNK pathway
B. The sympathetic nervous system
(7274). One more key parameter in the interrelationship
The SNS is intimately linked to metabolic control, es- between obesity/adiposity and inflammation is adiponec-
pecially in response to stress, and hence can play a major tin levels. Adiponectin belongs to the family of adipocy-
role in the maintenance of homeostasis during aging. Ag- tokines and is a protein that is exclusively secreted from
ing alters SNS function (57) and therefore limits the re- adipose tissue, with circulating levels inversely propor-
sponsiveness of older organisms to external stimuli. In tional to body fat, and that would present anti-inflamma-
particular, efficient responses driven by the SNS involve tory properties. However, adiponectin levels are reduced
both physiological and behavioral adjustments. For ex- in the case of obesity-induced low-grade chronic inflam-
ample, in response to external stressors, mice can adopt mation, thus perpetuating inflammation (75). It should be
different reproductive strategies either active or pas- noted, however, that high levels of adiponectin could con-
sivein part driven by the SNS activity (58). fer protective effects on insulin sensitivity. A major deter-
Cold triggers increased sympathetic tone enhancing minant may be the capacity of the adipose tissue to store
nonobligatory thermogenic mechanisms. BAT metabo- fat reserves effectively. If the capacity is limited, excess fat
lism and heat production are increased through -adren- will be deposited ectopically (ie, in muscle or liver) and
ergic stimulation and production of uncoupling protein 1 interfere with peripheral insulin sensitivity.
(UCP1). TH-dependent regulation of these processes has The HPT axis is proposed to interfere with inflamma-
been consistently demonstrated in different models (59 tory signals because JNK modulates TRH expression in
62), the SNS being a major player in TH control of the hypothalamus (see Section IV.B) (68). As well, adi-
metabolism (63). Besides local effects of -adrenergic- pocytokine levels are modulated with HPT axis function
induced cAMP stimulation of Dio2 and consequent in- (76). For example, leptin, which is considered a proin-
creased production of T3 that dose-dependently stimulates flammatory cytokine, regulates thyroid function at the
UCP1 transcription (64), T3 acts also at a central level to central level and can be reciprocally regulated by THs in
rats. Furthermore, resistin, another proinflammatory cy-
modulate SNS tone. A major recent finding in this context
tokine, is also regulated by THs in rats (76).
is the discovery in rats that intrahypothalamic TH mod-
Inflammatory markers often augment with aging as re-
ulates AMP-activated protein kinase (AMPK) activity (65)
flected by increased inflammatory markers and monocyte
and lipogenesis, resulting in modulated SNS output and
concentrations in aged mice (77). Intriguingly, high adi-
increased BAT thermogenesis. This increased thermogen-
ponectin levels are associated with increased life span in
esis is postulated to increase whole-body energy expendi-
model organisms such as Ames dwarf mice (78, 79), which
ture (65). In particular, the role of pro-opiomelanocortin is quite counterintuitive with respect to longevity if high
neurons within the arcuate nucleus in short-term response adiponectin is associated with high TH levels.
to cold challenge has been associated with increased TH
signaling (66). Furthermore, liver D1 activity is also reg- 2. Immune response, TH homeostasis, and aging
ulated via the SNS (Figure 6), with -adrenergic blockers Close links exist between the SNS and the immune sys-
decreasing plasma T3 levels and inhibiting liver conversion tem, particularly when considered in the context of met-
of T4 to T3 (67). abolic-associated chronic inflammatory diseases (62).
Moreover, the role of the HPT axis in immune activity is trol of GHRH (stimulation) and somatostatin (inhibi-
quite well documented (for instance, see Ref. 80), but few tion). GH stimulates growth, cell reproduction, and
studies have addressed how aging affects these interac- regeneration in humans and other animal species mainly
tions. Upon activation of the mouse immune system, after by stimulating the production of IGF-I, which in turn ex-
bacterial lipopolysaccharide injection, involving IL-1 (81) erts a negative feedback on the pituitary and the hypo-
and IL-12 (82), Dio1 expression decreases in pituitary thalamus along with circulating levels of GH to suppress
and liver, whereas Dio2 is increased in hypothalamic central production of GH. Furthermore, TH increases GH
tanycytes, with TH levels decreasing 24 hours later (81, gene expression and secretion via effects on the hypothal-
82). Because increased hypothalamic D2 activity will re- amus and pituitary in both rats and humans (86, 87). The
inforce negative feedback and TRH repression, this pro- link between growth and longevity is well established in
vides a double-pronged, central, and peripheral brake on animal models, such as GH receptor knockout (KO) mice,
production of active T3. which exhibit decreased GH activity and the highest life
Appropriate immune response to pathogens, via adap- span of any laboratory mouse model (88, 89). Also, re-
tive immunity, depends on the ability of immune cells, moval of the pituitary, eliminating secretion of endocrine
namely lymphocytes, to react and proliferate. This prolif- signals such as GH, TSH, and prolactin, increases life span
erative capacity is much higher in hyperthyroid and lower (23). Other studies have shown that body weight of young
in hypothyroid compared to euthyroid mice, and it impli- individuals correlates inversely with longevity in a group
cates TH effects on the protein kinase C pathway (83). of heterogeneous mice along with IGF-I, leptin, and THs
In this field, it has been well documented that numerous (90). In contrast, the relation between the somatotroph
interactions occur between the HPT and hypothalamo- axis and longevity in humans is much more controversial.
pituitary-adrenal axes with respect to communication Berryman et al (21) extensively reviewed the role of hor-
with immune systems in the CNS. Although these inter- mones involved in growth processes and aging, so this will
actions have been extensively reviewed by Taub (84) and not be discussed in detail here.
because they have yet to be directly linked to aging pro- Many of the effects of GH are mediated through
cesses, they will not be discussed further here. IGF-I in mammalian models, another pathway tightly
The innate immune system is driven by endogenous linked to longevity. As with GH, interactions between
toll-like receptors (TLRs). These receptors recognize IGF-I and TH are numerous. T3 effects at the hypotha-
pathogen-associated molecular patterns, which result in lamic and pituitary levels drive production of IGF-I
activation of immune defenses such as lymphocyte prolif- mRNA (91, 92). Insulin/IGF-I signaling has been char-
eration. TLR4 is expressed on rat thyroid cells and medi- acterized as a predictor of longevity in Caenorhabditis
ates their response to lipopolysaccharide (85). Other de- elegans, Drosophila melanogaster, and mice (9395). A
tails of TLR implications in the HPT axis are lacking; recent study using data from 32 strains of mice showed
however, this result suggests that it could be possible that a significant correlation between low IGF-I levels and
the HPT axis-immunity/inflammation influence on aging increased longevity (see Section I.B) (46). Taken to-
does not act uniquely through the adaptive immune gether, these ideas suggest that GH, IGF-I, and TH sig-
system. naling pathways interact, with TH potentially having
an as yet not fully recognized role in determining lon-
D. Growth pathways and insulin signaling gevity. Questions remain as to which pathways are the
1. Growth pathways drivers and which are the responders. Answers will no
Many of the interactions between the TH and GH path- doubt depend on the levels of analysis (physiological,
ways were characterized in the early 1990s, as reviewed by cellular, or molecular) and on the tissue and develop-
Rodriguez-Arnao et al (4). Briefly, GH release by the pi- mental stage considered.
tuitary somatotropic cells is under the hypothalamic con-
2. Insulin signaling
The hypothalamus inte-
Box 1: Fuel for life: A central role for mitochondria in aging theories. Mitochondria grates afferent signals convey-
play a central role in several theories of aging. Mitochondria produce toxic products, ing information on current
reactive oxygen species (ROS), whilst performing their primary role as an energy energy balance, including nu-
producing organelle (234). ROS are known to damage DNA and result in oxidation trient-sensing mechanisms
of DNA and proteins (235, 236). In Box 2 6 are briefly described main theories of linking energy balance with
aging involving mitochondria, with respect to their chronological appearance. the other hypothalamic-con-
trolled physiological func-
tions (96, 97). Most research on insulin concerns peripheral Such processes involve direct transcriptional effects
effects, but increasing evidence suggests that insulin also has through THR and THR, but also indirect effects
a role in the central regulation of energy homeostasis (98, 99). through the SNS, as in the liver. Indeed, TH-derived
Besides varying as a function of glycemia, insulin levels hypothalamic stimulation of sympathetic outflow to the
change in proportion to adipose tissue in most mammals, liver modulates hepatic glucose metabolism (116 118).
and intracerebroventricular insulin administration results in Increasing evidence supports a predominant role of de-
a dose-dependent reduction in food intake and body weight iodinases in the onset of insulin resistance (119). Recent
(100). Insulin receptors are widely expressed in the mamma- studies described altered glucose and insulin signaling
lian brain (101), high levels being found in the olfactory bulb, in mice with targeted deletion for Dio2 (120, 121) and
hypothalamus, pituitary, hippocampus, and cortex. Al- Dio3 (122). Such interactions between TH and insulin
though the precise function of insulin signaling in these re- signaling will influence the propensity to obesity and
gions is largely unknown, recent data indicate that insulin insulin resistance during aging and might offer potential
feeds into a negative feedback loop for postprandial inhibi- targets for therapeutic approaches, especially in hu-
tion of feeding in the hypothalamus (99). Insulin signaling in mans (see Section V).
the hypothalamus is also required for suppression of endog-
enous glucose production by the liver (102, 103) and stim- E. Synchronization to light-dark cycles
ulation of lipogenesis in adipose tissue (104). Insulin also Homeotherms, ie, individuals capable of maintaining
enhances cognitive function, memory, and mood, possibly stable body temperature regardless of external conditions,
via effects on corticolimbic structures (105107) where it are strongly synchronized to light-dark (LD) cycles (123),
modulates synaptic plasticity, neurotransmitter release, and inducing daily variations in many biological functions,
neuronal survival (108). The relationship between peripheral including activity/rest, metabolism, temperature, and hor-
and brain insulin levels remains elusive. In rats, plasma in- monal rhythms. With regard to the HPT axis, circulating
sulin levels decrease in response to fasting and sharply in- TSH exhibits very robust daily rhythms in animal models
crease upon refeeding, whereas in the brain (olfactory bulb) (124). In this context, recent data show that Dio2 and
Dio3 are inversely regulated by the circadian clock in rats
an opposite profile is seen (109). The central role of the brain
in insulin action has received much attention, with experi- and are highly light responsive (125). Circadian rhythms,
ments assessing the effects of intracerebroventricular or in- ie, the approximate 24-hour oscillations in behavior and
tranasal administration of insulin on cognitive and metabolic physiology, rely on a conserved transcriptional-transla-
tional autoregulatory loop that generates molecular oscil-
functions (110). In particular, it was reported that intranasal
insulin delivery could decrease the peripheral neurotropic lations of clock genes at the cellular level (126). The
effects (111) or protect cognitive function (112) in experi- hypothalamic suprachiasmatic nucleus is the central pace-
mental rodent models of diabetes. maker in mammals, centrally regulating downstream os-
There is evidence for associations between TH levels cillators in peripheral tissues, thus ensuring proper central
and insulin signaling in animals (Figure 6). Indeed, T3 and peripheral synchronization of organismal functioning
levels increase with the onset of insulin resistance in to LD cycles (Figure 6). Among the potential critical in-
T2DM (113), and increased hepatic glucose production teractions between clock genes and metabolism involving
and reduced hepatic insulin sensitivity have been ob- TH signaling, one can cite the involvement of JNK path-
served with increased TH signaling (114, 115). In par- ways (for more details on JNK action, see Section IV.B) in
ticular, THs, along with catecholamines, stimulate glu- the regulation of Per1 expression mediated by noradren-
coneogenic enzymes and glucose production (116). aline in spinal astrocytes (127).
Multiple factors link pho-
toperiod and TH signaling at
Box 2: Rate-of-living theory the central, hypothalamic
Statement - High metabolic rate Decreased life span. and pituitary levels. Melato-
Origin - First introduced in 1908 by Rubner and later conceptualized by Pearl in 1928 nin and TSH converge on
(237). cAMP signaling, leading to
Experimental support - Total energy available for life is genetically predetermined; antiphasic activities and op-
thus increased use of energy results in shorter life span (237). posing functions in the pars
Limits - There is strong experimental evidence that conflicts with this theory (238 tuberalis (128). Production
241), suggesting that reduced energy expenditure might contribute, but cannot ex- of TSH in the pars tuberalis
clusively encounter for decreased lifespan. can be activated through the
photoperiod-dependent
stimulation of melatonin-responsive cells (129). Many di- F. Hormesis, caloric restriction, and mimetics
rect or indirect links exist between components of the TH There is increasing interest in approaches that could
cascade and clock genes, underlying the importance of decrease the damaging effects of metabolic activity,
thyroidal signaling in circadian rhythmicity (125, 130). whether through limiting energy expenditure and ROS
Melatonin also drives the daily variations in TSH in rats production or by improving detoxification and autophagy
(124), the peak of TSH occurring at the beginning of the properties. Moderate chronic caloric restriction (CR),
dark phase. Such tight daily TSH rhythms could mod- without malnutrition, has been proposed to increase life
ulate whole body metabolism, and age-related drift span, but also and more importantly to retard age-related
would alter homeostasis responses. Besides links to cir- diseases in a number of species, both invertebrates and
cadian cycles, TSH directly triggers photo-induced vertebrates (157, 158). Nevertheless, it remains far from
breeding in Japanese quail (131) and THs are thought to clear whether reduced oxygen radical accumulation itself
be involved in seasonal acclimation in mammals accounts for extended longevity because the Gems group
(132135). did not see direct positive effects of superoxide dismutase
Aging is accompanied by homeostatic impairment of overexpression on longevity in C. elegans (159). It should
circadian rhythmicity (136, 137), entailing consequences also be noted that fasting, which is obviously an acute and
on central, endocrine, and metabolic functions. In partic- extreme form of CR, results in a rapid drop in circulating
ular, activity/rest rhythms are disturbed during aging, re- TH levels (160). Therefore, some other potential targets,
ducing robustness of dissociation between periods of ac- such as reduced TH signaling that could contribute to
tivity and periods of sleep (138 140). Following this line reduced ROS, should be explored. Data have been used to
of argument, a clear effect of aging on TSH rhythmicity is argue that hyperthyroidism results in increased ROS pro-
assumed, notably characterized by reduced amplitude and duction, which could provide a causal link with aging
phase advance of observed peaks (141143). Aging affects (161). However, this remains under debate because the
synchronization to LD cycles at multiple molecular and threshold of ROS required to negatively impact aging re-
physiological levels (144 146). More precisely, it was remains to be more clearly defined.
cently shown that membrane properties and GABAergic At the cellular level, CR reduces cellular senescence in
postsynaptic current amplitude were altered with age in mice (162) and oxidative stress in cultured neuronal cells
the suprachiasmatic nucleus at the single-cell level and (163), retards cerebral aging in nonhuman primates (164),
could therefore account for whole-body desynchrony has beneficial effects on body composition in humans
(147). For example, sleep is frequently disturbed in aged (165), and ameliorates many biomarkers of aging in mice
individuals, and there is strong evidence showing that (166), nonhuman primates (167), and humans (168). At
stress and GCs interfere with sleep patterns (148). Al- the molecular level, recent results show that specific genes
though poorly understood, metabolic processes and sleep involved in metabolic function and aging such as Sirtuin 1
patterns influence each other, which is best exemplified by (Sirt1), the mammalian target of rapamycin (mTor), or
the frequency of sleep disorders in overweight and obese p66Shc are modulated by CR (169 172). Overall, apply-
individuals (138, 149 153). Interestingly, THs seem to ing CR results in the general inhibition of these different
interfere with sleep patterns (154) in hypothyroidism factors (Sirt1, mTor, p66Shc) which is equivalent to placing
(155) and hyperthyroidism, notably by the regulation of the organism under moderate chronic stress, as opposed to
neuropeptide S (156). acute stress that would not have the same down-regulating
incidence. Paradoxically,
placing the organism in such
Box 3: Free radical theory moderate stress provides ad-
Statement - Increased ROS Decreased life span. vantages in slowing down
Origin - Harman (1956), and later modified in 1972. the rate of aging and there-
Experimental support - Increased metabolism results in increased ROS and thus fore limiting the risks of age-
increased DNA damage, ultimately resulting in decreased life span. This assumption associated diseases. This
is supported by a number of data, notably that production of ROS in mitochondria mild-stress status can be
is higher in older individuals (244) and less mitochondrial metabolism results in an linked to the recently de-
increased life span in a number of different organisms (245). scribed concept of horme-
Limits - Recent data suggest that ROS are not the primary cause of aging, even though sis (173177). This term,
contributing to it (246, 247), therefore seriously putting into question the actual role first used in ecology, denom-
of ROS in the aging process (247249). inates the inverted-U shaped
dose-response curve of stress
on fitness (173). Indeed, under moderate intensity, a stres- transcription in mice (198), there is no real consensus
sor can induce positive effects on fitness and survival. In about the significance of metformin supplementation on
contrast, above a certain limit, stress becomes deleterious. longevity in rodent models (199). It is worth mentioning
Given the characteristics of hormetic responses, biogeron- here the stimulatory effect of ghrelin release on fT4 levels
tologists have recently proposed that the hormesis model combined with the decreased levels of TSH in humans
could aid in understanding the positive effects of moderate (200), underlining a ghrelin-mediated effect upon TH ac-
CR stress on health and longevity (175, 178 180). This tivity in response to food intake. Although this finding has
state of stress acclimatization is beneficial in mice, with not been linked to aging effects, it could be hypothesized
short-term CR increasing resistance to ischemia (181). An that in the context of CR, lesser food intake results in
interesting parallel has even been drawn between CR and decreased ghrelin-stimulated TH release.
the induced lowering in body temperature, thus suggesting Recently, branched-chain amino acids were described
that chronic exposure to mild cold stress could have ben- to exert a variety of positive effects in animals and humans,
eficial effects on longevity (182, 183). Although the ap- more particularly on cardiac and skeletal muscle mito-
plication of the hormetic model in gerontology remains chondrial biogenesis. Beneficial effects on oxidative dam-
controversial (184), there is an indication that chronic age and physical endurance in middle-aged mice were also
moderate stress could potentiate the plasticity of individ- described, resulting in prolonged survival (201). Interest-
uals and optimize their capacity to face environmental ingly, like CR, resveratrol supplementation modulates TH
changes. signaling, but in this case by paradoxically increasing cir-
Alternative strategies are to find molecular mimetics culating TSH (202, 203) or T3 levels (204).
that activate the same pathways as CR, via dietary sup-
plementation, therefore avoiding changes in energy intake G. Thyroid hormones, stem cell renewal,
(185). Although the link between CR and TH status has and tissue regeneration
yet to be explored, proposed mimetics include 2-deoxy- The concept that TH signaling modulates timing of cell
D-glucose (186), a less readily metabolized glucose, and division and differentiation decisions during organogen-
resveratrol (185), a natural polyphenol, has shown prom- esis and development was established in the early 1950s
ising, if not consistent, results on energy metabolism ho- with studies in a number of species. Most work focused on
meostasis and longevity (187191). Rapamycin, targeting the nervous system, with TH being shown to affect neu-
the mTOR pathway, also induces positive effects on lon- rogenesis, neuronal differentiation, synaptogenesis, and
gevity in cell systems and rodents (192, 193), mainly via neuroplasticity, as well as affecting development of glia,
autophagy potentiation (185, 194, 195). In addition to notably controlling oligodendrocyte differentiation. Later
effects in the periphery, insulin sensitizers, such as the per- investigations linked TH signaling to early development of
oxisome proliferator-activated receptor (PPAR) ago- many other tissues, including the intestine, bone, muscle,
nist rosiglitazone may enhance insulin-mediated processes and sensory organs (eyes, ears).
in the brain. Preliminary results have shown improvement More recently, and simultaneously with the discovery
of memory function in patients with Alzheimers disease of stem cells in adult tissues, interest has grown in TH
upon treatment with rosiglitazone (196). Another com- effects on these cell populations, with TH being shown to
pound acting on insulin signaling is metformin, already contribute to regulating adult stem cell function in the
used as an antidiabetic drug to suppress gluconeogenesis brain, muscle, and intestine (205208). A common feature
and improve insulin sensitivity (197). Although met- of stem cell niches is their complex cellular composition
formin administration has shown CR mimetic effects on and architecture. In the adult mammalian brain, 2 stem
cell niches are found in the
subventricular zone and the
Box 4: Mitochondrial decline theory hippocampus (206, 209). In
Statement - Decreased mitochondrial function Decreased life span (derived from both areas, slowly dividing
the Free radical theory). neuronal stem cells give rise
Origin - First proposed by Harman in 1972 and refined by Miquel in 1980. to a population of rapidly di-
Experimental support - Mitochondria provide ATP to the whole organism, which viding progenitor cells that
serves as fuel for metabolic reactions, but also for repair and regeneration processes. then differentiate into mi-
With age, mitochondria decay and become less efficient (mtDNA damage, less ATP grating neuroblasts. TH sig-
produced, reduced membrane efficiency, etc.), therefore reducing the efficiency of naling affects cell division
each organ (251253). and differentiation in both of
the neural stem cell niches
(206, 209). Similar cellular hierarchies (stem cell/progen- tissues, including skeletal muscle (213, 214) and the ce-
itor/differentiated cells) are found in the intestine and hair rebral cortex of the developing rat (215, 216). One major
follicle stem cell niches (207). player of the nucleus-mitochondria cross talk in the reg-
In each of these cases, the core questions are where and ulation of mitochondrial transcription by THs has been
in which cell populations (stem cells per se or transient recently identifiedp43, a truncated but ligand binding
amplifying progenitors) THRs are expressed and how is form of THR1 specifically localized in mitochondria.
TH availability controlled in the niche, ie, which cells ex- This THR is T3-responsive and acts as a transcription fac-
press which deiodinases and which cells respond to TH by tor at the level of the nuclear or mitochondrial genome to
activating or repressing genes implicated in regulating the stimulate mitochondrial biogenesis (217). Interestingly,
transitions. p43 KO mice exhibit altered insulin secretion and severe
Despite the complexity of the systems, a number of glucose intolerance under HFD/high-sucrose diet feeding,
common features seem to be emerging that could have probably explained by altered pancreatic function (218),
important consequences for the understanding of TH sig- which contrasts with the improved insulin sensitivity ob-
naling and tissue regeneration, and hence the maintenance served in THR null mice (219). Additionally, the same
of tissue homeostasis during aging. The central idea that group demonstrated that skeletal muscle development and
seems to be emerging, but that still requires much detailed function were markedly affected by overexpression or de-
experimental validation, is that the actual stem cell pop- letion of p43, providing a novel perspective to TH action
ulation requires low levels of TH to maintain its stemness on muscle (217, 220). These findings show that p43 and
and renewal capacity. This state contrasts with the active thus T3 share an important role in the control of glucose
TH signaling observed in the rapidly amplifying progen- and insulin signaling.
itor cell pool where, as in oligodendrocytes during early Mitochondriogenesis is reduced during aging (221).
development, TH and THR together will control the PPAR coactivator-1 (PGC-1), a coactivator of PPAR-
switch from active cycling to differentiation (210). dependent transcription, is also implicated in TH regula-
tion of mitochondrial biogenesis. PGC-1 coactivates sev-
eral transcription factors, including THR, and its
expression is activated endogenously by T3 via the TH
IV. Metabolic/Molecular Targets of Thyroid
Signaling Linked to the Aging Process responsive element present on its promoter (222). T3-me-
diated gene expression is not perturbed by an inactivation
TH being a main modulator of metabolism in homeotherms, of PGC-1 activity and is thus not dependent on PGC-1
it is vital to understand how TH-dependent central and pe- (222), suggesting that mechanisms exist that compensate
ripheral metabolic controls change during aging. for T3 signaling via PGC-1. An inverse relationship also
exists because PGC-1 can influence splicing of THR
A. Mitochondrial activity RNA transcripts (223). Observations in PGC-1 KO mice
THs increase metabolism and thermogenesis through found similarities in the response to exercise as found in
multiple direct and indirect, central and peripheral mech- aged mice, suggesting a critical role for this coactivator in
anisms. Given the tight links between TH signaling and age-related reduction of mitochondriogenesis (221). Al-
metabolic levels, understanding the negative correlations though promising, further research is required to elucidate
between TH levels and longevity must include a focus on the interactions of T3 and PGC-1 in mitochondrial bio-
this level, notably in terms of mitochondrial function. TH genesis and their relationship with the aging process. In
controls mitochondrial biogenesis and function via mul- addition to mitochondriogenesis, PGC-1 has been high-
tiple mechanisms. For example, single injections of TH in lighted as a potential cross talk signal between nuclear and
vivo induce nongenomic and genomic changes (for review, mitochondrial aging pathways. Telomeres, long repeated
see Ref. 211) resulting in enhanced mitochondrial oxygen sequences found on the end of chromosomes, shorten as a
consumption rates (212). function of age, and a recent study has shown that re-
lengthening of these sequences by reactivation of the te-
1. TH signaling and mitochondrial biogenesis and function lomerase enzyme in aged mice can reverse tissue degener-
Thyroid status affects mitochondrial biogenesis and ation (224). Although telomere and mitochondrial
function, with TH directly regulating transcription of dysfunction have both been shown to affect aging, they
genes in the nuclear and mitochondrial genome, as well as have largely been studied separately. However, recent
potentially modulating mitochondrial function through studies in telomerase-deficient mice have provided evi-
nongenomic mechanisms (for review, see Ref. 211). Hy- dence for an intimate link between these 2 processes. Telo-
pothyroidism decreases mitochondrial biogenesis in many mere dysfunction causes a strong p53-dependent repres-
sion of PGC-1, therefore altering mitochondrial oxidative stress, and induction of cellular senescence,
biogenesis and function (225). Furthermore, a role of potentially impacting longevity (229, 231) (see Box 3).
PGC-1 in regulating p53-mediated cell fate decisions in However, an alternative hypothesis has been proposed
response to metabolic stress has been demonstrated (226). (232)the uncoupling to survive hypothesis (see Box
Additionally, PGC-1 is underexpressed in animals sub- 5). Unlike the rate of living free-radical damage the-
ject to perinatal hypothyroidism (216). Thus, the strong ory, the uncoupling theory postulates that increased
interactions between PGC-1, p53, and TH provide fur- metabolism could favor a longer life span by greater
ther potential mechanisms by which the HPT axis can uncoupling proton transport across the inner mitochon-
interact during aging, thereby affecting homeostatic con- drial membrane from ATP synthesis and reduced ROS
trol of metabolism. production (232). Such uncoupling with greater energy
metabolism with less ROS has been associated with lon-
2. Mitochondrial activity and aging ger life span in mice (233). As mentioned above, Bla-
Mitochondria, as major contributors to the mainte- gosklonny (184, 227) recently proposed that ROS
nance of energy homeostasis, are a focal point in aging should not be considered as a driver of aging itself,
studies and the focus of a number of aging-related theories because most living organisms do not live long enough
(see Box 1). Links between TH and longevity have often to age from oxidative damage. Instead, this author fa-
been sought at the level of mitochondrial metabolism, vors the hypothesis of overactivated signal-transduc-
more particularly production of ROS and oxidative dam- tion pathways (including the mTOR pathway; see be-
age caused by metabolic processes such as adaptive ther- low) as determinant modulators of longevity (184).
mogenesis. This approach still holds, even if ROS signal-
ing as a primary cause of aging is a matter of current debate B. Activation/silencing of the JNK pathway
(227). BAT is a main thermogenic source in homeotherms JNK1 is a kinase stress and nutrient sensor activated in
(228) and is activated in response to cold by T3-dependent response to circulating fatty acids or inflammatory mark-
mechanisms (see Section III.B) (229). Recent studies in ers and cytokines (269). JNK1 deficiency in the nervous
rodents have shown that T3-dependent UCP1 expression system of mutant mice markedly increases TRH and TSH
in mitochondria of BAT drives heat production inde- (270).
pendently of shivering or other muscle generated pro- In rodents, a HFD increases hypothalamic JNK1 activ-
cesses (230). THs up-regulate UCP1 expression in BAT ity (68, 271), which is associated with increased proin-
directly via stimulation by THR or indirectly by SNS flammatory signals, decreased hypothalamic insulin re-
activation originating from a T3-stimulated drop in sponsiveness, and insulin resistance (68, 271). JNK1 KO
AMPK activation in the ventromedial hypothalamus mice are resistant to HFD-induced complications such as
(65). The resulting small, but whole-body increase in hyperglycemia, hyperinsulinemia, and insulin resistance
temperature will accelerate general metabolic processes (272). Pituitary- and brain-specific JNK1 KO mice treated
throughout the organism. T3-dependent activation of on HFD have increased T3 and oxygen consumption and
UCP1 is not limited to BAT. UCP1 activation in adi- decreased lipid load in BAT (271). The unexpected in-
pocytes increases glucose and fat metabolism, and as creased expression of TRH and TSH in JNK1 KO mice,
with any metabolic process, the resulting toxic products with regard to the expected negative feedback control of
including free radicals could result in ROS production, elevated T3 and T4, indicate that JNK1 negatively regu-
lates the HPT axis (270).
JNK1 activation also re-
Box 5: Uncoupling-to-survive theory duces insulin and IGF-I sig-
Statement - Increased uncoupling activity Increased life span. naling (273), thus promot-
Origin - Brand (2000). ing life span extension and
Experimental support - This theory proposes a predominant role for uncoupling stress resistance through re-
proton transport across the inner mitochondrial membrance from ATP production, duced activity of metabolic
in order to reduce ROS production, and therefore reduce the oxidative damage and growth signaling path-
caused by mitochondrial activity. Uncoupling requires uncoupling proteins, which ways. Indeed, JNK1 KO
use the proton leak to produce body heat (232, 233, 254 256). mice have increased pitu-
Limits - To date, this theory has not been contested. The potent role of UCPs in itary GHRH and thus
human metabolism has even been proposed as a pertinent strategy to limit obesity higher GH and IGF-I secre-
(257263). tion. This effect on GH,
combined with its effect on
the HPT axis (Figure 6), would potentially favor a de- ulate TRH neurons, cannabinoid receptor 1 was shown to be
crease in life span (270, 271). This has been shown in present in both inhibitory and excitatory axons innervating
flies, where JNK1 activation was associated with re- the TRH neurons, thus suggesting that the TRH neurons can
duced growth and an increase in life span (274). Increased regulate their own excitatory and inhibitory inputs via the
JNK1 activation in flies is also known to increase resis- retrograde endocannabinoid signaling system (280).
tance to oxidative and cellular stress, which are 2 of the Recent studies in C. elegans showed that dietary re-
better defined drivers of aging (275). Thus, an overall in- striction decreases NAEs, such as anandamide, and in-
crease in JNK1 results in a potentially increased life span, creases life span (281). The same study provided the
whereas a short-term acute response such as that in ro- reciprocal demonstration that increasing NAE levels de-
dents fed a HFD results in life span-reducing secondary creases life span, supporting the hypothesis that these
effects. Furthermore, associations between life span and metabolically responsive signaling molecules act on
JNK activity have been made based on data from studies in growth and life span pathways (281). Evidence for the
Drosophila and, because JNK is conserved between species, role of endocannabinoid signaling in the regulation of
the life span effects could also be conserved (276). aging in higher organisms such as mammals has not yet
been obtained. However, the conservation of NAEs
C. Role of N-acylethanolamines and endocannabinoids
across organisms could suggest that their age-influenc-
N-Acylethanolamines (NAEs) such as anandamide (N-
ing effects may also be conserved, although the in-
arachidonoylethanolamine) and 2-arachidonoyl glycerol
creased NAEs after fasting in mammals contrast with
(2-AG) are the most abundant endocannabinoid signaling
data in C. elegans (278).
molecules found in the CNS. These molecules activate the
cannabinoid receptor CB1, a G protein-coupled receptor
D. Selenium, TH signaling, and aging
found on presynaptic axons (277). Endocannabinoids are
Selenium, a trace element obtained from dietary intake,
central signaling molecules that respond to the dietary
is vital to many aspects of thyroid function. Selenoen-
state of the organism. Studies in rat limbic forebrain and
zymes, such as glutathione peroxidases, can limit the po-
hypothalamus confirmed that the levels of these mole-
tential toxicity of ROS by catalyzing secondary reactions
cules, predominantly 2-AG, were increased in response to
such as the reduction of hydrogen peroxide to water, after
fasting, with a decrease upon refeeding (278). The authors
superoxide dismutase conversion of the ROS O to H2O2
also demonstrated an increase in food intake stimulated by
(282). Selenium, as selenocysteine, is also incorporated
2-AG injections into the rat limbic forebrain. When pe-
into the iodothyronine deiodinases and is required for the
ripherally administered, endocannabinoids cause de-
correct functioning of these enzymes (283). The deiodi-
creased circulating levels of TSH, T3, and T4 (279), thus
nases control the bioactivity of TH by either permitting the
synchronizing a decrease in food intake with a decrease in
conversion of inactive T4 to active T3 or inversely T3 de-
TH-controlled energy expenditure (Figure 6). In addition,
activation. TH and serum selenium are part of a feed-
although it remains unclear how endocannabinoids reg-
forward regulation involving the activity of THR1 and
selenoproteins, each partner
affecting the regulation of
Box 6: Mitohormesis the other (284). In addi-
Statement - Moderate, chronic ROS production Increased life span. tion, a meta-analytical study
Origin - Tapia (2006) found that deiodinases, in
Experimental support - Increased ROS as a response to low-level stress permits an particular D1 and D2, are
increase in resistance to potential oxidative stress. CR and physical exercise increase implicated in selenium defi-
life span which is assumed to be due to an increase in ROS (174, 264). Studies in ciency-associated diseases
model organisms have shown that endogenous induction of free radicals can extend of aging in mice, highlight-
life span (264). Thus, the resistance to stress, which develops from chronic low-level ing their importance in el-
exposure to ROS, results in a protective anti-aging strategy. derly populations where defi-
Limits - The model of hormesis, based on the inverted-U shaped dose-response, ciency can often occur (285).
remains controversial, especially when it comes to radiation (265). Indeed, the com- In humans, selenium defi-
monly accepted linear no-threshold model of dose-response in radiobiology assumes ciency in individuals over 65
a strictly linear dependence between the risk of radiation-induced adverse health years old is associated with
effects and radiation dose. However, this assumption is also questionable, as ben- less peripheral T3 produc-
eficial effects after ionization have been described in different models (266 268). tion from T4 and is also a risk
factor for autoimmune thy-
roid disease (AITD), a disease state that can negatively and were more related to the genetic background of the
affect health span (286). The author concluded that in strains used.
conditions of low selenium, the multiple essential seleno- Furthermore, SIRT1 is involved in a number of dis-
proteins (including D3) as well as 1 nonessential seleno- eases, including T2DM (298). Increasing evidence links
protein (ie, D1) are prioritized to maintain HPT axis func- circadian clocks and SIRT1 (299, 300) with a proposed
tion. Such processes meet the rationale of the triage role in the aging process (301, 302). SIRT1 plays a role in
theory that argues for a crucial role of dietary availability regulating cellular senescence, along with AMPK activity
in vitamins and minerals and the prioritization of their (303). Wang et al (303) proposed a model in which the
partitioning in accordance with organismal needs (287 switch from cellular presenescence to irreversible senes-
289). Although these findings highlight the importance of cence results from concomitantly decreased SIRT1 expres-
the HPT axis in the light of mineral prioritization, it does sion/activity and increased AMPK function.
not explain the detrimental effects of selenium deficiency The role of SIRT1 as a deacetylase is also of interest
on health. Indeed, modest selenium deficiency has been because TH signaling implicates changes in chromatin and
associated with age-related deficiencies (Figure 6), includ- histone acetylation/deacetylation. All the main THR iso-
ing cancer, heart disease, and immune dysfunction (285). forms (THR1, THR1, and THR2) when unliganded
interact with histone deacetylases 1/2/3 in a corepressor
E. Aging-associated genes and TH signaling complex including nuclear receptor corepressor and si-
The multifactorial aspects of aging render the identifi- lencing mediator for retinoid or THRs, thereby negatively
cation of specific genes responsible for age-associated al- regulating gene expression in the absence of TH (304).
terations difficult. Despite this, a number of genes in- Surprisingly, few studies have addressed links between
volved in energy homeostasis have been linked to aging SIRT signaling and TH. However, SIRT1 KO mice display
processes (55, 290). Rather than playing independent an interesting regulation of TSH secretion (305) because
roles in the aging phenomenon, these genes are thought to SIRT1 is highly expressed in pituitary thyrotrope cells. In
interact, thereby contributing to aging. thyrotrope cells, enzymatic activity of SIRT1 controls
As mentioned earlier, GH/IGF-I signaling plays a major TSH release, thereby regulating TH secretion and metab-
role in longevity in various species, notably in mice (10). olism. Indeed, it was found that SIRT1 positively regulates
Because integration of these pathways occurs at multiple exocytosis from TSH-containing granules from thyro-
levels, in the hypothalamus and pituitary and in peripheral tropic cells in the anterior pituitary via deacetylation of
tissues, the somatotroph axis will interact with multiple phosphatidylinositol-4-phosphate 5-kinase . The
pathways. Main candidates include KLOTHO, mTOR, deacetylated form of phosphatidylinositol-4-phosphate
and Sirtuins. The following sections address how TH sig- 5-kinase is more enzymatically active, and the phospha-
naling could interact with these pathways. tidylinositol-4,5-biphosphate synthesized the secretion of
TSH from pituitary thyrotropes (305).
1. The sirtuin family
Sirtuins are nicotinamide adenine nucleotide-depen- 2. The mTOR pathway
dent deacetylases that are conserved from bacteria to hu- Another extensively studied, aging-related pathway is
man. The sirtuin family has been extensively studied after the mTOR cascade (306), the mTOR1 and mTOR2 com-
the demonstration that activation of SIR2, a member of plexes being critical regulators of cellular metabolism,
the sirtuin family in yeast, positively affects longevity growth, and proliferation (307). mTOR integrates the in-
(291). Since then, the link between sirtuins and longevity put from upstream pathways, including insulin and IGF-I,
has been confirmed in other species, including humans but also senses cellular nutrient and energy levels and re-
(292). SIRT1, the mammalian homolog of SIR2 and the dox status (308). Use of various genetic models shows the
first of the 7 members of the sirtuin family, is involved in implication of this pathway in regulation of energy ho-
the control of energy homeostasis (293), but also in the meostasis via nutrient and stress-sensing properties (308).
regulation of inflammation and stress response, neuronal Decreased activity of mTOR signaling extends life span in
and cardiovascular function, cancer, and epigenetics yeast, C. elegans, and D. melanogaster (309). Following
(294). Although some studies have shown that SIR2 over- the same trend, genetic deletion of S6 kinase 1, a kinase
expression induced by dietary restriction increases life substrate of the mTOR pathway, in mice (S6K1 KO mice),
span in C. elegans and D. melanogaster (295, 296), these prolongs life span in females and retards the appearance of
findings were brought into question in a study in which the age-associated disease (310). Interestingly, there is evi-
effects of dietary restriction on longevity were shown to be dence for regulation of the mTOR cascade by SIRT1, the
independent of SIR2 overexpression in these species (297) latter negatively modulating mTOR activity (311).
Until recently, no studies had addressed potential cross interactions between TH signaling and the aging process
talk between TH signaling and mTOR on metabolic proin humans.
cesses. It is known that the mTOR pathway affects thy-
rocyte proliferation (312) and that inhibition of mTOR by 1. Consequences of impaired TH function on
insulin/IGF-I signaling
rapamycin treatment resulted in increased iodide uptake,
thus showing a role of mTOR in normal thyroid cell func- Overall, as with animal models, homeostatic mainte-
nance is impaired during aging and leads to impaired neu-
tion (193, 312), and thus confirming earlier studies (313).
ronal plasticity and altered cognitive function. It also re-
However, a recent paper identifies a role of mTOR acti-
sults in greater frailty toward environmental changes
vation in the hyperphagic response of hyperthyroid rats in
(321323). Given the numerous interactions and cross
association with increased expression of agouti-related
talk between systems that have to be taken into account
peptide and neuropeptide Y, and decreased levels of pro-
when assessing the effects of one endocrine system on an-
opiomelanocortin mRNA in arcuate nuclei neurons (314).
other, notably during aging, the difficulty is always deter-
Central inhibition of the mTOR pathway of hyperthyroid
mining cause and effect. However, one can note for the
rats with rapamycin reversed the hyperphagic phenotype
current discussion that in humans, hyperthyroidism leads
and induced body weight loss (314). These results identify to the development of insulin-resistant phenotypes (324)
a first level of interaction between TH and mTOR, but and reduced glucose tolerance (325), mainly caused by
given the links, for instance, between mTOR signaling and enhanced gluconeogenesis.
ROS production (315), other cross talk or common end- In addition, individuals with hypothyroidism exhibit
points might well be discovered. low circulating IGF-I and low IGF-I activity (326). In ad-
dition, a clinical study involving 800 children with short
3. KLOTHO
stature revealed that the children whose height was asso-
Klotho, a gene accidentally discovered by Kuro-o et ciated with lower IGF-I levels had decreased T3 (327).
al (316), encodes a transmembrane protein associated
with fibroblast growth factor 23. Succinctly, klotho acts as 2. TH and circadian rhythmicity
a regulator of mineral metabolism and growth factor sig- Daily rhythms of rest/activity and core temperature
naling (317). Klotho modulates aging in mice (318, 319), are particularly altered with age in elderly people (140,
deficiency leading to shortened longevity, associated with 323, 328).
disorders similar to human premature-aging syndromes With regard to the HPT axis, TSH exhibits very robust
(316). Conversely, transgenic klotho mice, ie, mice over- daily rhythms in humans, with no effect of gender on TSH
expressing klotho, show life span increases of 20 30% secretion patterns in healthy adults (329). Population-
(26). Unexpectedly, this phenotype is accompanied by based studies have revealed inconsistent results as to how
IGF-I and insulin resistance, which is contradictory with the regulation of the HPT axis changes with aging, espe-
improved insulin sensitivity observed in GH-deficient cially regarding the role of TSH. Possibly due to the in-
mice and more generally delayed-aging models (318). creased prevalence of subclinical hypothyroidism with
Bartke (318) proposed that klotho could inhibit IGF-I and age, TSH levels are often found to be increased in elderly
insulin ligands, thus reducing their signaling and posi- subjects (330). Also, studies using frequent blood sam-
tively affecting longevity. Mizuno et al (320) have re- pling throughout the 24-hour cycle show inconsistent re-
ported a positive effect of T3 on klotho transcription in sults. In carefully screened healthy euthyroid men, both
3T3-L1 adipocytes during differentiation. Thus, if and basal TSH secretion and TRH-induced TSH secretion
how TH signaling affects klotho pathways could be a fer- were found to be decreased in the elderly men, whereas
tile area of investigation. TSH rhythm persisted with similar timings of the noctur-
nal acrophase and daytime nadir (331). Although the ab-
solute amplitude was reduced, the relative amplitude did
V. Clinical Data Linking TH to Longevity not significantly change with age (331). Moreover, al-
though basal levels of T3 (but not T4) were found to be
A. Experimental data in humans confirm the existence lower in elderly men, the TRH-induced increases were
of TH/longevity cross talk similar, suggesting that the aged thyroid is still capable of
Many of the general concepts observed in animal mod- responding adequately to acutely increased TSH (331).
els discussed in the previous sections are supported by Also, in another study, basal levels of TSH and free T3
experimental and epidemiological data from human stud- (fT3) (but not fT4) and TRH-induced TSH secretion were
ies. Here, we selected a few relevant examples to illustrate found to be decreased in elderly subjects (332). However,
in this study in which authors controlled for negative thy- of TSH. During illness unrelated to the thyroid gland, thy-
roid peroxidase antibodies, a gender effect was observed roid signaling is constrained through decreased TH or
because the blunted TSH response to TRH was most pro- TSH secretion and reduced T4-to-T3 conversion (345). In
nounced in males (332). In contrast, in another study addition, enhanced T3 degradation by neoexpression or
(329), only women exhibited a positive correlation be- elevation of Dio3 activity is also a major contributor to the
tween TSH levels and age, meaning that older females had euthyroid sick syndrome (reviewed in Ref. 346). Inflam-
higher levels of TSH than their younger counterparts. The matory cytokines, such as IL-6 and C-reactive protein
subjects in this study were free of acute or chronic disease (CRP), were found to increase with age. This result was
and did not use thyroid disease medication. However, this confirmed in aged adults, using 2 cohorts of individuals
study did not control for thyroid peroxidase antibodies. In aged over 72 or over 85 years, where increased CRP and
humans, TSH peaks at the beginning of the dark period IL-6 were moderately associated with a decline in cogni-
and is lowest in the middle of the afternoon. However, tive function (347, 348). Thyrotoxicosis induced by clin-
TRH and fT4 levels do not appear to be rhythmically ical states such as hyperthyroidism also correlates with
regulated in healthy humans (333). In contrast, fT3 shows increased inflammatory cytokines such as IL-6 and IL-8
a circadian rhythm that is delayed but parallels TSH levels (349). Considering the fact that hyperthyroidism is asso-
(334). Moreover, fT3 levels also show seasonal variation ciated with bone resorption, it was proposed that high
and are generally higher in winter (335). Sleep is fre- levels of TH could stimulate bone loss through IL-6 pro-
quently disturbed in aged subjects, and there is strong ev- duction in bone marrow stromal and osteoblast-lineage
idence showing that stress and GC interfere with sleep cells, thus favoring the age-associated disease osteoporosis
patterns (336). Conversely, sleep disturbance affects me- (350, 351).
tabolism. Sleep depth decreases both glucose tolerance Release of adipokines, adipose-derived cytokines, such
and overall 24-hour mean TSH concentrations (337). It as adiponectin, is negatively correlated with total body fat
has been proposed that the capacity to maintain optimal and positively correlated with T4 (352354). Indeed, ad-
melatonin signaling (ie, robust daily variations) through- ipose tissue plays a major role in the maintenance of energy
out life could predict extended longevity (338). In addi- homeostasis, and its absence such as in familial partial
tion, improving regularity in daily routine (eg, meal times, lipodystrophic syndromes results in adipokine dysregula-
bed times) could be a therapy itself; reinforcement of day/ tion as well as insulin resistance (355). Furthermore, high
night discrimination with light therapy has also been adiponectin is associated with increased life span in cen-
shown to induce beneficial effects on health (339). Chro- tenarian humans (356). In a clinical study on aged humans
notherapy is a recent concept that aims to take into ac- (ages 5570 y), TH levels within physiological ranges were
count circadian rhythmicity of organismal endocrine positively correlated with a number of active immune cell
function when replacing hormones (340, 341). Recently, types such as memory T-helper lymphocytes and nega-
it has been shown that compared to levothyroxine taken tively correlated with naive components of the immune
in the morning on an empty stomach, levothyroxine system (357). In general, this would suggest that those
taken at bedtime improved TH levels significantly bet- individuals with higher circulating T4 and T3 concentra-
ter in patients with primary hypothyroidism (342). The tions had previously experienced a higher activation of
neglect of such interaction between chronobiology and their immune system. This utilization of the immune sys-
therapeutic strategies might underlie some of the con- tem would, in theory, result in decreased immune cells and
troversies on this subject, which is particularly the case therefore immune responsiveness available later in life.
with TH replacement (343). Data from studies including the Leiden 85-plus Study in
aged individuals suggest that high preserved levels of T3
3. Stress response, immune system, and inflammation are associated with a maintained immune response with
The data on the cross talk of TH signaling with the age (358).
immune system is one in which the data are probably bet- Other than the proliferative abilities of the adaptive
ter understood in human rather than rodent or other an- immune system, aspects of the innate immune system are
imal models. One of the most studied areas is that of re- also largely implicated in aging, as described by Shaw et al
duced TH signaling in severe disease, nonthyroidal (359). A combination of studies have confirmed that TLR
illness syndrome, also known as euthyroid sick syn- function (ie, pathogen recognition and immune response
drome or low T3 syndrome (for review, see Warner and activation) becomes progressively impaired as a conse-
Beckett, Ref. 344). The laboratory parameters of this syn- quence of aging in humans, and some single nucleotide
drome include low serum levels of T3, high levels of rT3, polymorphism variants of TLRs have even been associated
with normal or low levels of T4 and normal or low levels with a longer life span (359).
Table 1. Risk of Mortality in Participants Aged 90 Years Based on Baseline Levels of TSH and fT4 (n 271)
Participants With
Crudea Adjustedb Normal TSH Levels Onlyc
TSH
HR (95% CI) 0.85 (0.74 0.97) 0.83 (0.71 0.95) 0.91 (0.711.16)
P value 0.019 0.009 0.44
fT4
HR (95% CI) 1.25 (1.08 1.44) 1.19 (1.04 1.36) 1.14 (0.94 1.38)
P value 0.003 0.011 0.19
fT3
HR (95% CI) 0.85 (0.70 1.04) 1.17 (0.971.42) 1.46 (1.06 2.12)
P value 0.11 0.10 0.021
Abbreviations: HR, hazard ratio; CI, confidence interval.
a
Sex-adjusted hazard ratios for mortality were estimated using Cox regression and are presented per standard deviation increase of 0.97 mIU/L log TSH, 2.92 pmol/L
for fT4, and 0.82 pmol/L for fT3.
b
Adjusted for baseline disability and health status (including levels of albumin and CRP, Mini Mental State Examination score, and subjective health).
c
Normal TSH levels are defined as between 0.3 and 4.6 mIU/L.
Finally, a strong connection between the thyroid axis higher TSH levels at the age of 90 years were also associated
and autoimmune diseases is known to exist, with the prev- with better survival during follow-up (Table 1). To exclude
alence of AITD being 5% of the general population (360). confounding by baseline differences, we additionally ad-
This connection could be attributed to the production of justed for differences in baseline disability and health status,
immunological factors such as cytokines (IL-1, IL-6) and estimated from plasma levels of albumin and the inflamma-
expression of receptors such as the homing receptor CD44 tory marker CRP, cognitive ability as assessed by the Mini
and intercellular adhesion molecule 1, which can all be Mental State Examination, and subjective health. Finally, the
implicated in the development of an immune response analyses were restricted to participants with serum TSH lev-
against components of thyroid activity (361). AITD is els within the reference range. With regard to fT3 contribu-
largely influenced by genetic susceptibility and environ- tion, a trend is observed for increased fT3 levels to associate
mental factors including stress, medical interventions, in- with decreased old age mortality in the crude analysis (Table
fection, and pollutants (360, 362). Data also show that the 1). When we correct for the contribution of the nonthyroidal
quantity of thyroid autoantibodies is higher in aged sub- illness syndrome by adjustment for parameters related to ill
jects, which increases AITD risk (363). Individuals who health, the trend reverses toward a trend for increased fT3
are particularly affected are those who are hospitalized or levels to associate with increased old age mortality. The as-
in the general elderly population (364), whereas this in- sociation of increased fT3 and increased mortality reaches
creased AITD risk is rarely observed in long-lived aged
statistical significance when we additionally restrict the anal-
individuals such as centenarians (365).
ysis to subjects with TSH levels within the reference range
(Table 1).
B. Human population studies: TH and longevity
Many endocrine signals, including circulating TH lev- In a population of independently living elderly men,
els, decrease with age in humans (17, 366) and rodents higher fT4 was associated with lower physical function
(367). Such observations lead to 2 main questions: first, (369). Further work, largely based on the Leiden Longev-
are the decreases the causes or consequences of the aging ity Study, demonstrated that low TH activity is related to
process; and second, are decreased serum levels of TH prolonged life span in humans. Nonagenarians from par-
favorable for extended longevity? A series of epidemio- ents who reached an exceptionally high age had higher
logical studies link lowered circulating TH to increased TSH levels and lower circulating TH levels when com-
longevity (368 373). Notably, Westendorp and col- pared to nonagenarians whose parents died at younger
leagues (371, 372) observed that slightly higher TSH levels ages (371). Moreover, the middle-aged offspring of these
were associated with a survival advantage (371) without ap- nonagenarians also showed a tendency toward higher cir-
parent negative effects on ability or mood in a population- culating TSH levels and lower circulating TH levels as
based sample of late octogenarians (372). To investigate compared to their partners (373). In a subgroup of par-
whether the survival advantage associated with higher TSH ticipants from whom we had fasted blood samples, we
extends to higher ages, we also determined TSH and TH found that offspring showed higher TSH levels as well as
levels at the age of 90 years in the same cohort. In line with a tendency toward lower peripheral TH levels as com-
our observations at the age of 85 years, we observe that pared to their partners (Table 2). Taken together with the
Table 2. Endocrine Serum Parameters After Overnight Fast for Offspring From Long-Lived Families and Controls
Offspring Controls (Partners) P Value
Participants, n 121 113
Age, y 63.9 (58.9 67.9) 62.2 (58.9 67.7) 0.33
Females, n (%) 62 (51.2) 59 (52.2) 0.90
TSH, mU/L 2.41 (1.933.06) 1.69 (1.332.15) 0.029
fT4, pmol/L 16.2 (15.8 16.6) 16.4 (16.0 16.9) 0.49
fT3, pmol/L 5.03 (4.875.20) 5.26 (5.09 5.44) 0.045
GH, mU/L 1.90 (1.50 2.40) 2.02 (1.58 2.57) 0.72
IGF-I, nmol/L 15.3 (14.316.2) 15.0 (14.116.0) 0.71
IGFBP-3, mg/L 4.03 (3.85 4.21) 3.98 (3.79 4.16) 0.63
Cortisol, mol/L 0.49 (0.47 0.52) 0.52 (0.49 0.55) 0.22
Prolactin, U/L 10.1 (9.28 10.9) 10.3 (9.5111.2) 0.64
hsCRP, mg/dL 1.29 (1.171.60) 1.17 (0.931.46) 0.45
Abbreviations: IGFBP-3, IGF binding protein 3; hsCRP, high-sensitivity CRP. Data are given as mean (95% confidence interval), except for age, which represents median
(interquartile range); and TSH, GH, and hsCRP, which are given as geometric mean (95% confidence interval). All blood samples were taken between 9 and 9:30 A.M.
Results were adjusted for sex and age.
observation of higher circulating TSH levels in the off- in elderly subjects (379). TSH levels are known to grad-
spring of centenarians (368), these observations imply that ually increase with age, a shift that extends into advanced
lower activity of the HPT axis is a heritable phenotype that age (330). Recently, it was shown that the higher TSH
contributes to exceptional longevity. In accordance with levels observed at old age might partly result from selective
previous findings (374), we did not find significant differ- survival of subjects with constitutionally low thyroid
ences in IGF-I serum levels between the offspring and their function (368). Thus, whereas some of the changes in thy-
partners. Moreover, a single time-point measurement af- roid function that are observed upon aging may be part of
ter overnight fasting showed similar levels of serum GH, age-related pathology, others may actually occur in re-
serum cortisol, and prolactin, as well as hsCRP. sponse to the accumulation of damage and may instead
Subclinical hypothyroidism is diagnosed when the se- represent adaptive mechanisms aimed at delaying age-re-
rum TSH concentration is above the upper reference limit lated pathology. Although differences exist between coun-
and fT4 remains within the reference range. The preva- tries, the prevailing recommendation is to treat elderly
lence of both subclinical hypothyroidism and subclinical patients with subclinical hypothyroidism with TH sup-
hyperthyroidism increases with age (375). Subclinical hy- plementation. However, the issue of reversing the endo-
pothyroidism has been associated with several negative crine changes that occur during human aging by treatment
clinical outcomes, most notably an increased cardiovas- of (subclinical) hypothyroidism remains highly controver-
cular risk, particularly in those with TSH concentrations sial. Although pathological changes might benefit from
of 10 mIU/L or greater (376). Other negative clinical out- treatment, changes in thyroid function that are part of an
comes that have been associated with subclinical hypo- adaptive response or constitutively low thyroid function
thyroidism include reduced bone density, cognitive de- might not. A systematic review of available clinical trials
cline, and increased risk of overt thyroid dysfunction. It is could not demonstrate improved survival or reduced car-
interesting to note that a recent meta-analysis evidenced diovascular morbidity after levothyroxine replacement
detrimental effects of subclinical hypothyroidism (includ- therapy for asymptomatic subclinical hypothyroidism
ing coronary heart disease) in young adults, whereas the (380). Further controlled, randomized studies in larger
risks were diminished or even suppressed in elderly people groups of elderly subjects are necessary to unequivocally
with high TSH levels (377). In line, it was reported in demonstrate whether or not treatment of subclinical hy-
another recent study that treatment of subclinical hypo- pothyroidism in old age confers health benefits.
thyroidism (TSH, 510 mIU/L) reduced the incidence of
fatal and nonfatal ischemic heart disease in younger sub- C. Rejuvenating strategies in humans
jects (ages 40 70 y) but not in older subjects (70 y) As in animal models, rejuvenating strategies, including
(378). This ambiguous relationship between subclinical CR, dietary supplementation, or tissue regeneration, have
hypothyroidism and disease risk probably remains the shown promising results in humans. For example, CR in-
main source of controversy for the treatment of subclinical duces beneficial effects on body composition in humans
hypothyroidism in aging populations. (165) and ameliorates many biomarkers of aging (168).
Indeed, there is no consensus on the TSH cutoff values Given these advantages, observed from nematodes to pri-
that should be used as indicators for treatment, especially mates (381), CR has been proposed as a potential strategy
Figure 7.
Figure 7. Schematic view of the interactions between THRs and key players of metabolism, growth, and inflammation pathways. Using Genomatix
Pathway System (GePS), we extracted a list of candidate genes that can link TH signaling to aging and are discussed in the review. This summary
schema is extracted from a series of more complex, if not exhaustive networks (Supplemental Figures 1, 2, and 3) that were generated and
provides a schematic view of the known interactions entertained between TH receptors (THRA and THRB) and the 3 major biological systems
involved in maintenance of homeostasis and aging (metabolism, growth, and inflammation). Schemas of this type have been generated for both
mice and humans. Genes that are functionally related and involved in the same pathway are grouped in boxes representative of metabolism,
growth, and inflammation functions, respectively. All genes represented in these networks have direct interactions with THRA (red lines), THRB
(blue lines), or both. These interactions represent an original set of data that has never been published before.
to retard age-related metabolic impairments in humans supplementation (eg, resveratrol, rapamycin), targeting
(382384). One contribution of CR-induced metabolic genes involved in the human aging process, such as Sirt1
improvement in humans could be mediated by the bene- (292294, 301, 302) and mTor (307309), could also be
ficial effects of CR described on mitochondrial biogenesis verified in humans (185, 189, 190, 387). However, it
(385). The proposed beneficial effects of mild-stress sta- should be noted that the use of such drugs in human ther-
tus, following the concept of hormesis already described, apeutics is so far limited due to the adverse effects of rapa-
could be verified in humans too (175177), and poten- mycin treatment for example, including hyperglycemia
tially render biogerontologists optimistic about the ex- and dyslipidemia (388). Similarly, intranasal drug delivery
pected effects of moderate CR stress on human health and has received much attention these last few years because it
longevity (175, 178). Furthermore, it has been proposed bypasses the blood-brain barrier and ensures an efficient
that hormesis underlying T3 action may constitute a novel route to target specific pathways (389, 390). For example,
preconditioning strategy for ischemia-reperfusion injury intranasal insulin modifies whole-body energy homeosta-
during liver surgery (386). The calorigenic effect of T3 on sis (110, 391) and improves cognitive function (110, 112,
liver increases ROS production, up-regulating inflamma- 392394) in humans. Also, the resveratrol-derived mod-
tory factors such as nuclear factor-B and cytokines, as ulation of TH signaling observed in animal models holds
well as antioxidant enzymes. These responses represent for humans (202).
hormetic effects, re-establishing redox homeostasis, pro- Finally, interest in TH effects on stem cells in adult
moting cell survival, and protecting the liver against isch- mouse tissues (395) seems relevant to humans, too, be-
emia-reperfusion injury (386). The advantages of dietary cause TH regulates adult stem cell function in human hair
follicles (396). Dysregulation of TH availability, either too the mechanisms underlying the incidence of inflamma-
much or too little, will either exhaust the stem cell popu- tion, growth, and metabolism in long-lived humans as
lation precociously or contribute to pathological amplifi- compared to short-lived rodent species.
cation. Two potential examples of the latter situation in- Most probably, these views will evolve rapidly in par-
clude colon cancer (397) or glioblastoma where TH allel with advances in molecular biology and genetics and
signaling has frequently been incriminated (398). the advent of new large-scale strategies such as metabo-
lomics and genome-wide association studies (399). How-
ever, by highlighting first the negative correlations be-
VI. TH Signaling and Key Biological tween TH levels and aging, and second some common
Aging-Linked Processes elements between TH signaling and certain theories of
aging, we argue that better knowledge of the complex
In this review, we have examined data from rodent and interactions between thyroidal signaling and homeostasis
human studies that show how THs, as key controllers of maintenance will in turn advance our understanding of
metabolism, growth, and inflammation, integrate homeo- longevity.
static maintenance and thereby modulate the aging pro-
cess. To better visualize the multiple regulatory metabolic,
growth, and inflammatory processes that THs, and more Acknowledgements
specifically their receptors (THR and THR), affect ei-
ther directly or indirectly, we exploited the Genomatix Address all correspondence and requests for reprints to: Barbara Deme-
neix, Musum national dHistoire Naturelle, Laboratoire de Physiologie
Pathway System (http://www.genomatix.de). Figure 7 is a
Gnrale et Compare, Unite Mixte de Recherche, Centre National de la
much-simplified summary schema from a series of original Recherche Scientifique 7221, 75231 Paris cedex 5, France. E-mail:
and more complex, if not exhaustive networks that were bdem@mnhn.fr.
generated (Supplemental Figures 1, 2, and 3, published on Work in our laboratories is supported by the European Community
The Endocrine Societys Journals Online web site at http:// within the Seventh Framework Program under grant agreement no.
Health-F2-2010-259772. Research on the Leiden 85-plus Study and the
edrv.endojournals.org) for humans (Supplemental Fig-
Leiden Longevity Study is supported by the Netherlands Genomics Ini-
ures 1A, 2A, and 3A) and mice (Supplemental Figures 1B, tiative/Netherlands Organization for Scientific Research (NGI/NWO;
2B, and 3B). Each link is established from published ex- 05040202 and 050-060-810, NCHA).
perimental evidence obtained on either human or mouse Disclosure Summary: R.G.J.W. is a principal investigator of a ran-
models and shows direct regulations between THRs and domized controlled trial into the effect of substituting thyroid hormone
in patients with subclinical hypothyroidism (TRUST Thyroid Trial), an
certain genes (either genes regulated by THR or vice
EU FP-7-financed project. All other authors have nothing to declare.
versa). As shown in Figure 7, THRs are tightly linked
(either activating, inhibiting, or modulating) to the ex-
pression of key regulators of metabolism (including
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Thyroid Hormone Signaling and Homeostasis

J. Bowers,* J. Terrien,* M. S. Clerget-Froidevaux, J. D. Gothie, M. P. Rozing,

I. Introduction IV. Metabolic/Molecular Targets of Thyroid Signaling

I. Introduction and maturation (13, 14). It is noteworthy that the timing

Figure 2. of TH changes over life span, with a

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