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ABSTRACT. Resveratrol, the naturally occurring polypheno-
lic compound characterized by anti-oxidative, anti-inflam-
matory and apoptotic properties, appears to contribute sub-
stantially to cardioprotection and cancer-prevention. In ad-
dition, resveratrol is believed to regulate several biological
processes, mainly metabolism and aging, by modulating the
mammalian silent information regulator 1 (SIRT1) of the sir-
tuin family. Resveratrol may arrest, among various tumors,
cell growth in both papillary and follicular thyroid cancer by
activation of the mitogen-activated protein kinase (MAPK)
signal transduction pathway as well as increase of p53 and its
phosphorylation. Finally, resveratrol also influences thyroid
function by enhancing iodide trapping and, by increasing TSH
secretion via activation of sirtuins and the phosphatidylinos-
itol-4-phosphate 5 kinase γγ(PIP5Kγγ) pathway, positively af-
fects metabolism.
(J. Endocrinol. Invest. 34: 788-792, 2011)
©2011, Editrice Kurtis
INTRODUCTION
Resveratrol (3, 4, 5-trihydroxytrans-stilbene) is a polyphe-
nol found in considerable amounts in the leaves, stems,
seeds, and skin, though not the flesh, of grapes and, with
considerable regional variations, also in the fruits of bilber-
ries as well as lowbush and highbush blueberries (1, 2). In
nature, the compound plays a key role in plant defense by
acting as a phytoalexin generated as a by-product of stress
caused by pathogens such as bacteria or fungi. In this con-
text, ectopic production of resveratrol via molecular engi-
neering in plants is aimed at enhancing the anti-fungi re-
sistance mechanism by increasing antioxidant activity (3).
Today, resveratrol is the focus of considerable scientific in-
terest due to its observed beneficial effects on various hu-
man diseases, e.g. cardiovascular disease, cancer, and di-
abetes (4). This new awareness arose in the 1990’s when it
was established that resveratrol intake, via moderate wine
consumption, produces a cascade of positive biologic ef-
fects involving cellular signaling mechanisms that trigger in-
teractions at the genomic level, this resulting in decreased
atherogenesis and inhibition of athero sclerosis (5). In ad-
dition, interest in its potential health effects has been fur-
ther promoted with the detection of trans-resveratrol glu-
curonides, and not of the free form of the molecule, in hu-
man serum, whether these are produced by means of di-
etary intake of resveratrol or are a simple product of the an-
tioxidant pool contained in red wine (6, 7). Meanwhile, re-
cent in vitro studies have identified resveratrol as a natural
antioxidant, possessing free radical scavenging activity, as
well as the fact that it elevates apolipoprotein A-1 (apoA-
1)-mediated cholesterol efflux and suppresses oxidative
stress (8). Furthermore, resveratrol may suppress oxidative
and inflammatory stress response to a high-carbohydrate,
high-fat meal by stimulating the activity of the antioxidant
transcription factor NF-E2 related factor 2 (Nrf-2) (9). These
antioxidative effects of resveratrol in the post-prandial state
is likely related to its antiatherogenic properties and pos-
sibly contribute to reduction of the incidence of cardio-
vascular disease and mortality.
Meanwhile, it has recently been reported the apparent
ability of resveratrol to increase iodide trapping in thyroid
cells offers hope that this polyphenol compound could
potentially be utilized as a drug in thyroid disease (10).
The aim of this paper is to review the effects of resveratrol
both on modifying aging and on thyroid function as well as
to outline the currently employed treatment modalities.
RESVERATROL AND THE “FRENCH PARADOX”
Red wine is considerably richer in resveratrol than white
wine, apparently due to the fact that polyphenols are ex-
tracted faster during the production process of white
rather than of red wine. Its abundant presence in red wine
has been proposed as comprising the main “factor” to
explain the so-called “French Paradox” (11). The term
“French Paradox”, which describes the low incidence of
cardiovascular disease in the French population despite
their high dietary intake of saturated fats, was introduced
in 1992 and constituted for many years an unresolved
phenomenon (12, 13). Despite the fact that the exact con-
tribution of wine alcohol to reduced risk of coronary heart
disease is unclear, procyanidins, its principal vasoactive
polyphenols, have been strongly associated with consid-
erable protective effects (14). Epidemiological data have
meantime been assembled suggesting that moderate red
wine consumption (10-20 g/day), in contrast to heavy al-
cohol consumption and binge drinking that are associat-
ed with highly adverse results, decreases the risk for coro-
nary heart disease mainly due to the synergistic effects of
wine components on inhibition of platelet aggregation
and atherogenesis (15). It has also recently been demon-
strated that the phenolic compounds of red wine inhibit
the oxidation of LDL, while resveratrol, in concomitance
with quercetin, another phenolic compound, blocks
Key-words: “The French-paradox”, resveratrol, sirtuins, thyroid, thyroid cancer.
Correspondence: L.H. Duntas, MD, Endocrine Unit, Evgenidion Hospital, 20 Papa-
diamantopoulou Str., 11528 Athens, Greece.
E-mail: ledunt@otenet.gr
Accepted August 25, 2011.
First published online September 23, 2011.
Resveratrol and its impact on aging and thyroid function
J. Endocrinol. Invest. 34: 788-792, 2011
DOI: 10.3275/7926
L.H. Duntas
Endocrine Unit, Evgenidion Hospital, University of Athens, Greece
SHORT REVIEW
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©2011, EditriceKurtis
FOR PERSONALUSEONLY
Resveratrol and thyroid
789
eicosanoid synthesis (16). It can thus be seen that the car-
dioprotective effect is multifaceted and evidenced by
both non-genomic and genomic effects (17, 18). In several
studies, resveratrol has exhibited anti-oxidant and anti-in-
flammatory actions and has therefore been used on a tri-
al basis as a therapeutic agent in neurodegenerative dis-
eases (19), while it has been shown, via trials implement-
ing dose (nanomolar concentrations) and time modula-
tion, to act as an anti-cancer compound through its inhi-
bition of cell growth of prostate cancer lines mediated by
the production of nitric oxide (NO) (20).
RESVERATROL BIOSYNTHESIS
Resveratrol is member of a family of enzymes, under the
general name of stilbene synthase, which make up part of
a large family of proteins with numerous functions in vari-
ous plants. It is noteworthy that its chemical structure pre-
sents distinct similarities with that of L-T4(Fig. 1). Stilbene
synthase (STS), which appears in plants as a consequence
of a stress factor, such as UV radiation and fungal infec-
tion, catalyzes the chemical reaction, thereby producing
resveratrol from a derivative of the amino acid phenylala-
nine (21). Besides resveratrol synthase, another well-de-
fined member of this protein family is chalcone synthase
which is the key enzyme in the production of flavonoids
and anthrocyanins. Resveratrol synthase is developed from
chalcone synthase via gene duplication and mutations (22).
The absorption of resveratrol in humans occurs by trans -
epithelial diffusion and amounts to about 75%, while tis-
sue accumulation enhances efficacy at target sites (23).
The rate of absorption in terms of C max and time of T
max is delayed by the presence of food, though the ex-
tent of absorption [area under the curve (AUC)] is not af-
fected and the figures do not appreciably change by re-
peated dose administration (24).
Trans-resveratrol, the active isomer form of resveratrol,
and its metabolites (resveratrol glucuronides and sul-
phates) along the epithelial cells are highly metabolized
in humans and, although their biovailability is very low
due to a rapid sulphate conjugation by the gastrointesti-
nal tract, they exert chemopreventive and anti-inflam-
matory activities (25).
In addition, there is some evidence that trans-resvera-
trol delays the onset of age-related diseases in mam-
mals and that it may extend life duration in a variety of
organisms (26).
The need for further development of analogs with im-
proved bioavailability, such as methylated derivatives of
resveratrol, for the purposes of clinical research is there-
fore pressing (27).
RESVERATROL AND AGING
Resveratrol has also been suggested as possibly pos-
sessing anti-aging properties, this having been demon-
strated in studies in which resveratrol extended the lifes-
pan of yeast, fruit flies, and roundworms (28, 29). One
area of major interest relates to the effects of resveratrol
on silent information regulators [sirtuins (SIRT)], a class of
nicotinamide (NAD) (+)-dependent histone deacetylases.
In yeast, high levels of SIRT2 promote longevity by me-
diating the effects of caloric restriction (CR), while in
mammals there are seven SIRT (SIRT 1-7) characterized
by diverse biological function (30). SIRT can control
metabolism by consuming NAD(+) and affecting the gen-
eration of ATP: they may thereby act as regulators of cel-
lular metabolism affecting fat mobilization and gluco-
neogenesis (31).
In humans, SIRT1 is the ortholog of the yeast SIRT2 im-
plicated in various cellular processes such as cell cycle
growth, senescence, apoptosis, stress response and ag-
ing (32-34). SIRT1 promotes free fatty acid mobilization of
fat from white adipose tissues by repressing peroxisome
proliferator-activated receptor-γ(PPARγ), a nuclear re-
ceptor that promotes adipogenesis. Resveratrol deacety-
lates PPARγthus increasing fat mobilization and mito-
chondrial size and number (35). Via this process, it acti-
vates SIRT which, by affecting multiple transcription fac-
tors, exert various positive effects on endocrine function
and metabolism and may hence extend lifespan (Fig. 2).
Moreover, it has been demonstrated that resveratrol pos-
sesses the ability to mimic the effects of CR, which has
been established as an effective anti-aging measure (36,
37). Indeed, diet supplement with resveratrol was able
to mimic short-term CR effects, including improvement
of glucose and lipid metabolism, by activating the fork-
head transcription factor (Fox01) which, activated by
phosphorylation, represses the activity of PPARγand pre-
vails as a key mediator of the actions of resveratrol (35).
Thus, due to this observed significant impact of SIRT1 on
metabolism, cardioprotection and chemoprevention, ac-
tivators of SIRT1 have been formulated as molecules which
may well have potential to enhance longevity (38, 39).
Since there is additionally evidence that SIRT1 improves
insulin sensitivity and lipid metabolism in Type 2 diabetes
mellitus (DM), it has been proposed that activators of SIRT1
may be of therapeutic value in Type 2 DM (40, 41).
Fig. 1 - The chemical structures of resveratrol and thyroxine, ex-
hibiting distinct similarity of the compounds.
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790
RESVERATROL AND THE THYROID
Resveratrol has been reported to arrest the cell growth of
human papillary (PTC) and follicular thyroid cancer (FTC)
via the mitogen-activated protein kinase (MAPK) signal
transduction pathway (42). MAPK activation by the phy-
toalexin is followed by an increase of an oncogene sup-
pressor protein, p53, and its phosphorylation at serines 6
and 15 in FTC and serine 15 in PTC (43). It is known that
phosphorylation of p53 at several serines determines the
biological activity of the protein and induces apoptosis
(44). Concomitantly, the polyphenolic compound in-
creases the levels of p21, a cyclin dependent protein ki-
nase inhibitor, whose rise leads to inhibition of DNA syn-
thesis and cell arrest, thus enabling the DNA repair pro-
cess (45). However, given that the increase of p21 mR-
NA by resveratrol is reduced by a p53 inhibitor, this in-
dicates a role for p21 in the p53-dependent apoptosis
ignited by resveratrol (44). Therefore, resveratrol induces
apoptosis in both thyroid cancer cell lines by promoting
phosphorylation of p53 at serines 6 and 15, although
phosphorylation of serine 6 is not apparently required
for the induction of apoptosis in PTC.
In an experimental study designed to assess the effects
over 3 months of resveratrol on the hypothalamic-pitu-
itary-thyroid axis in ovariectomized rats, it was shown that
serum levels of 0.1 and 8.1 µmol resveratrol significantly
increase T3levels, while no thyroid morphological changes
were observed (46). An indirect effect via SIRT1activation
or even via activation of the cAMP-responsive gene for
type 2 iodothyronine deiodinase, as was proposed for
kaempferol, another polyphenolic molecule (47), was pos-
tulated.
Recently, it was demonstrated that SIRT1 is abundantly
expressed in pituitary TSH secreting cells and that, by
manipulating its levels, resveratrol regulates TSH secre-
tion (48). SIRT1 overexpression or decrease (knockdown)
resulted in the respective increase or decrease in the
amount of TSH secretion into the medium. SIRT1 is the
binding partner and deacetylation substrate of phos-
phatidylinositol-4-phosphate 5 kinase (PIP5K)γand en-
hancer of PIP5Kγenzyme activity. SIRT1 knockdown abol-
ishes TSH secretion, while the SIRT1 mediated action on
TSH secretion is inhibited by PIP5Kc knockdown (Fig. 3).
It is of interest that SIRT1 KO mice had higher levels of
Fig. 3 - Resveratrol may regulate TSH secretion via activation of
sirtuin 1 (SIRT1) and the phosphatidylinositol-4-phosphate 5 ki-
nase (PIP5K)
γ
-PI4P pathway. SIRT1 deacetylates PIP5K
γ
, which
catalyzes the synthesis of PIP2in endocrine cell, this subsequently
activating TSH secretion by thyrotropes.
Fig. 2 - Resveratrol exerts a variety of ef-
fects by activating sirtuin 1 (SIRT1) and
modifying several transcription factors
thus influencing biological processes that
lead to lifespan extension.
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Resveratrol and thyroid
791
PIP5Kγand smaller pituitaries with greater TSH protein
content than wild type mice. However, the TSH secre-
tion from the thyrotrophs was significantly lower than that
of the wild mice, indicating that SIRT1regulates TSH via
the PIP5Kγpathway (48). Taking into account these re-
sults together with the fact that SIRT1activation improves
insulin sensitivity (49), the identification of the resvera-
trol-SIRT1-PIP5Kγ-TSH pathway is a major event in sci-
entific research into energy metabolism.
The influence of resveratrol on sodium-iodide symporter
(NIS) has, more recently, been studied in FRTL-5 cells
with regard to iodide uptake and NIS protein expression
(10). The component of the red grape increases the up-
take of radioiodine by 3.5-fold while simultaneously ele-
vating the NIS protein level by 3-fold, respectively. It is
noteworthy that resveratrol also increases NIS in a dose-
and time-dependent manner in TSH deprived cells. Nev-
ertheless, the molecular pathway remains unknown as it
is, in contrast to TSH, AMP independent. These study re-
sults are of great interest, especially for clinical thy-
roidology, due to the possibility of regulation of iodide
transport by resveratrol and thus its potential application
in the treatment of differentiated thyroid carcinoma re-
fractory to radioactive iodine. However, the magnitude
of the demonstrated iodide uptake of 66% does not re-
flect a curative dose for tumors with low levels of NIS and,
as has been stated in an editorial that accompanied the
study (50), it has not been demonstrated that orally ad-
ministered resveratrol in patients may have the same ef-
fects as in FRTL-5 cells. Consequently, more work is re-
quired before introducing resveratrol into clinical oncol-
ogy.
Moreover, resveratrol as an antioxidant agent is a free
radical scavenger and this property can be of interest in
thyroid disease states that are accompanied by increased
production of hydrogen peroxide and radical oxygen
species, such as autoimmune thyroiditis and hyperthy-
roidism (10). It therefore appears rational, though here
caution is recommended since uncertainty still remains
as regards its effectiveness in humans, to investigate
resveratrol’s actions, or analogs with more favorable ki-
netics, combined with methimazole in patients with
Graves’ disease.
EPICRISIS
Resveratrol is likely to possess remarkable anti-oxidative
properties, anti-inflammatory and anti-cancer activity,
lipid lowering effects and SIRT1 stimulating actions. As
a phytoalexin compound, resveratrol may be applied in
the manufacture of functional foods (51), hence providing
the public with valuable nutritive health choices. In addi-
tion, by activating sirtuins resveratrol offers potential for
development of a pluripotent drug for the treatment of
Type 2 DM and its complications, obesity, and various
other disorders (52).
It has also been determined that resveratrol may arrest
the proliferation of thyroid cancer cells by increasing the
abundance and phosporylation of p53. Moreover, resver-
atrol mediates the regulation of TSH while, due to its ef-
fects on iodine tapping, it shows promise as a prospec-
tive anti-thyroid drug. Studies are ongoing and, though
several demonstrate compelling evidence as to the safe-
ty and tolerability of resveratrol up to doses of 5 g/day,
additional research is certainly required to ascertain ef-
fectiveness in humans as well as to define the lowest dose
of action (53). Nevertheless, because of its low bioavail-
ability there is an imperative need for the design of mod-
ified resveratrol preparations (54) exhibiting the same
pattern of action while displaying more stable pharma-
cokinetics.
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