Thyroid Hormone

and Aging
Ketut Suastika
Divisi Endokrinologi dan Metabolisme
Bagian/SMF
Bagian /SMF Penyakit Dalam FK Unud
Unud--RSUP Sanglah
Sanglah,, Denpasar
The Hallmarks of Aging

Lopez-Otin dkk. Cell 2013; 153: 1194-1217.

 Physiology of
Thyroid Hormone
Figure. 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.

Bowers J et al. Endocrine Rev 2013; 34: 556-589

Simplified overview
of the HPT axis
Stimulation of the hypothalamus results
in TRH release, which increases TSH
secretion 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. 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 turn can be locally activated
into T3 by deiodinases D1 and 2.
Pathways of TH deactivation (involving
deiodinase D3) are not included in this
simplified schematic view of the HPT
axis, although their roles are of
particular importance in the brain for
example.

Bowers J et al. Endocrine Rev 2013; 34: 556-589

 Physiologic effects of thyroid hormones
◉ Fetal development
◉ Oxygen consumption, heat production & free radical formation

◉ Cardiovascular effects

◉ Sympathetic effects

◉ Pulmonary effects

◉ Hematopoietic effects

◉ Gastrointestinal effects

◉ Skeletal effects

◉ Neuromuscular effects

◉ Effects on lipid & carbohydrate metabolism

◉ Endocrine effects
Dysfunction of Thyroid
Hormone in The Elderly
Age--induced changes to thyroid function
Age
• Anatomical changes
• Atrophy-reduced weight and size of thyroid gland
• Reduced follicle size and colloid content, diffuse fibrous interstitial
expansion

Photomicrographs of haematoxylin and eosin stained sections of normal thyroid tissue in a

17-year-old (a) and a 58-year-old woman (b) at identical magnification (original magnification
×10). The follicles are generally of smaller size with a reduced amount of colloid as well as a
slight fibrous interstitial expansion in the older individual.

Boelaert K. Nature Rev 2013; 9: 194-204

Age--induced changes to thyroid function
Age

• Hormonal changes
• Healthy elderly: Age-dependent decline TSH, FT3,
increased rT3 (inactive form), normal FT4
• Jewish centenarians: higher TSH – survival, longevity
• Confounding factors
• Chronic illness (“non-thyroidal illness syndrome”): low
FT3, low or normal TSH, high rT3 and normal FT4
• Non-thyroidal illness syndrome: 32% in critical ill
hospitalized elderly patients

Asggarwal N and Razvi S. J Thyr Res 2013; http://dx.doi.org/10.1155/2013/481287.

Boelaert K. Nature Rev 2013; 9: 194-204
Gesing A et al. Thyr Res 2012; 5: 16-20
 Classification of Thyroid Dysfunction:
Biochemical Definition
TSH Level, by Condition Thyroid Hormones Comments
Overt hyperthyroidism
<0.1 mIU/L or undetectable Elevated thyroxine or
triiodothyronine
Overt hypothyroidism -
>4.5 mIU/L Low thyroxine
Subclinical hyperthyroidism -
<0.1 mIU/L Normal thyroxine and Clearly low serum TSH
triiodothyronine
0.1–0.4 mIU/L Normal thyroxine and Low but detectable
triiodothyronine
Subclinical hypothyroidism
4.5–10.0 mIU/L Normal thyroxine Mildly elevated TSH
≥10 mIU/L Normal thyroxine Markedly elevated TSH

Rugge JB et al. Screening and Treatment of Thyroid Dysfunction: An Evidence Review for the U.S. Preventive Services Task
Force. Ann Intern Med. 2014. doi:10.7326/M14-1456.
 Thyroid dysfunction in elderly
• Hypothyroidism
• Subclinical-Overt
• Subclinical hypothyroidism: associated with lower
mortality – lower metabolic rate – caloric restriction –
improve survival
• Overt Hypothyroidisms: impairment of attention,
concentration, memory, perceptual functions, language,
and executive functions
• Hyperthyroidism
• Subclinical hyperthyroidism: higher mortality –
increased risk for CHD and AF

Asggarwal N and Razvi S. J Thyr Res 2013; http://dx.doi.org/10.1155/2013/481287.

Boelaert K. Nature Rev 2013; 9: 194-204
Gesing A et al. Thyr Res 2012; 5: 16-20
 Diagnostic tests of nonthyroidal illness
vs subclinical hyperthyroidism
Subclinical
Laboratory tests Nonthyroidal illness*
hyperthyroidism‡
Normal or low or
TSH Undetectable or low
undetectable
Total T4 Normal or low Normal to high normal
Free T4 Normal or low Normal to high normal
Total T3 Low Normal to high normal
Free T3 Low Normal to high normal
Reverse T3 High Normal

*Treatment of underlying condition. No thyroid-specific treatment required.

‡Consider radioac ve iodine or antithyroid drug therapy if persistent.
Abbreviation: vs, versus.
Boelaert K. Nature Rev 2013; 9: 194-204
Thyroid Function
and Longevity
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).
Bowers J et al. Endocrine Rev 2013; 34: 556-589
 Correlations between total circulating T4 (tT4 in
mg/
g/dL
dL)) and median life span in a range of
mammalian species of different sizes

A, Small mammals maintained under domestic or laboratory conditions weighing between 0.025 and 30 kg (n=6); data included 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 kg. Data included jaguar, puma, ocelot, jaguarundis, margay, lion, elephant seal, llama, sheep,
bottlenose dolphin, and donkey. All tT4 data used were taken from young adults under regular 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 set of data that has never been published before.
 Cumulative Mortality of Participants Based
on Clinical Stratification of Thyroid Status

Plasma thyrotropin levels below 0.3 mIU/L were considered to be abnormally low; levels above 4.8 mIU/L were
considered to be abnormally high. Plasma free thyroxine levels below 1.01 ng/dL (13 pmol/L) were con- sidered to
be abnormally low; levels between 1.01 and 1.79 ng/dL (13 and 23 pmol/L) were considered to be normal.
Gussekloo J et al., J Am Med Assoc 2004; 292: 2591–2599
 Risk of Mortality in Participants Aged 90
Years Based on Baseline Levels of TSH and fT4
(n =271
=271))

Crudea Adjustedb Participants with

normal TSH levels
onlyc
TSH: HR (95% CI) 0.85 (0.74 – 0.97) 0.83 (0.71–0.95) 0.91 (0.71–1.16)
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 (0.97–1.42) 1.46 (1.06–2.12)
P value 0.11 0.10 0.021

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.

Bowers J et al. Endocrine Rev 2013; 34: 556-589

Rano A et al. ZambJ Cell Biol 2014; 204: 129-144
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.
NAE=N-acethylethanolamine;
JNK=c-Jun N-terminal kinase Bowers J et al. Endocrine Rev 2013; 34: 556-589