18. May 2010)
arrangement of pages
of this page was extracted from an excellent review: Alcaín and Villalba,
2009). A few references and comments were added.
Resveratrol is the main topic in another page in this website (more...),
and therefore there is no need here to discuss its structure and biosynthesis.
are many more publications on resveratrol effects found in in vitro
studies, and they implicate significant roles in many critical metabolic
processes, but here I will focus mostly only on those studies dealing with complete
organisms: that is (or probably should be) one of the major concerns for people
taking resveratrol, or are planning to do so.
A publication by
al. (2003) certainly was a key event in the development of the resveratrol
story: they studied the capacity of small natural molecules to stimulate sirtuin
activities. The screen with recombinant human SIRT1 led to the identification of several molecules, and resveratrol
turned to be the most active one. Others, but with lower activity, were another
stilbene (piceatannol), two chalcones (butein, isoliquiritigenin), and two flavonols (fisetin, quercetin)
(see Fig. 1). The yeast Sir2 recombinant sirtuin was also tested in vitro. Somewhat disappointingly, the effect of resveratrol with yeast Sir2 in
vitro was a
stimulation of only about twofold, much less than with the human SIRT1 (but our
interest is of course in people, not yeast!).
These assays measured the deacetylation of acetylated peptides conjugated to a
nonphysiological fluorophore. There are good reasons question
whether the effects of these natural products were really caused by
direct affects on the SIRT1 protein:
in vivo effects with yeast cells looked much better: butein, fisetin, and resveratrol increased
average life span by 31%, 55%, and 70%, respectively. Whatever the limitations
of these results are, many people were hypnotized by the 70% increase of life
span, and quickly started to calculate what resveratrol supplementation could
mean to human life extension.
Follow-up in the next years demonstrated similar life extension effects by
resveratrol in the
fruit fly (Drosophila melanogaster) and the
et al., 2004;
Viswanathan et al., 2005). However, this was disputed for both organisms in
at least two publications (Bass
et al., 2007;
al., 2008). One study even showed that resveratrol extended the lifespan of a
et al., 2006).
Natural SIRT1 activators, and links to pages in this website (Resveratrol,
Quercetin, Isoliquiritigenin =
6'-Deoxychalcone) or in
Fisetin; both pages are not
very informative, however).
The next important advance was the demonstration that resveratrol improved
health and survival of mammals (mice) on a high-calorie diet (Baur
et al., 2006). The significance is in the term 'high-calorie' diet, and the
implications for people: the
number of overweight or even obese people is steadily increasing,
apparently reaching the staggering number of 2.1 billion world-wide, with a
pretty high percentage in the Western countries. This is considered one of the
factors for many diseases, e.g. for cardiovascular disease and type 2 diabetes mellitus, and many more; these
are often summarized as 'metabolic syndrome'. The study showed that resveratrol
prevented the effects of excess calorie intake, that it shifted the physiology
towards the state of mice on a standard diet, and that it led to a significant increase
of survival. Comparable conclusions on the effects of resveratrol were reached by
One of the often discussed concerns about these experiments is the resveratrol
dosis: to the layman it looks awfully high in the Baur et al. (2006) experiments, but laymen are often not aware of the fact that amounts per mice
kilogram cannot simply be extrapolated to humans (more...).
More recent work (Barger
et al., 2008a) indicated that much lower concentrations of resveratrol are
likely to be sufficient to obtain many of the beneficial effects, and that even
short-term consumption can mimic at least partially the effects of a long-term
calorie restricted diet (Barger
et al., 2008b).
The application of resveratrol (or other substances with even higher activity,
see below) for treating the many problems of the metabolic syndrome was one of
the central themes in many recent studies (see Alcain
and Villalba, 2009 for a more detailed discussion, citation at end of this
page). In this context, these authors state that 'modifying the
dietary habits of populations will be extremely difficult'. It is therefore
probably only realistic (although certainly not the optimal solution) to look
for dietary supplements that mimic the effects of a low calorie diet. Clinical
studies on the effects of resveratrol on type 2 diabetes and other diseases are
supposed to be completed soon (November 2009). The review cited above also gives information on some
companies, their resveratrol preparations (e.g.
and numbers of the patents.
There are a few concerns with the application of resveratrol
Resveratrol is considered as a pharmacologically safe drug: it can be taken up to
5 g/day for 7 days without noticeable side effects (Elliott
and Jirousek, 2008; see also
Williams et al., 2009), but little seems to be known about possible side
effects in long-term applications.
The in vitro experiments with enzymes or tissues
indicate that about 10 to 200 µM resveratrol are necessary to elicit the
desired activation of SIRT1. However, this concentration is hardly reached
in the blood plasma even after application of very high doses of resveratrol.
Most of it is found very fast as glucuronide and sulfate
derivatives, and these appear to reach much higher plasma levels than the
resveratrol itself. It looks as if this should be investigated further, in
particular in their possible role of the derivatives in resveratrol effects.
A few simple stilbene derivatives were tested for improved
stability and bioavailability (Yang
et al, 2007), but it seems not clear whether they will be of practical
Taking resveratrol as supplement in whatever form
means that it principally should be available to all organs and cells, but
there is basically no evidence for that. Also, usually it is assumed tacitly
effects of sirtuins are the same in all cells/tissues, e.g. in
mediating the good effects of calorie restriction. Recent results, however,
indicate that SIRT1 regulation by calorie restriction is tissue specific, and not the same in all
et al., 2008). Can one predict with some reliability the consequences of
a system-wide activation of sirtuins? It may be possible that the results for systemic SIRT1
stimulation by resveratrol are more complex than understood so far. One example of the
complexity of sirtuin regulation, and complex effects of resveratrol and the
sirtuin inhibitor sirtinol is in this publication:
Pfister et al., 2008.
Down-regulation of p53
This protein plays an important role in
controlling growth of cells. Acetylation of p53 leads to its activation and
either growth arrest or apoptosis (programmed
cell death); this is a major factor in controlling tumor cells. It is
acetylated in the active form. SIRT1 binds to p53 and deacetylates it, i.e. it downregulates its activity and
delays or inhibits apoptosis (Vaziri
et al., 2001;
van Leeuwen and
Lain, 2009). This is good for the survival of normal cells, but
might also lead to increased survival and growth of tumor cells. In such
cases, resveratrol could have quite undesirable effects as tumor promoter, and the application
of SIRT1 inhibitors might be indicated instead (more...).
Validity of the tests for sirtuin activators (and
Most if not all of these assays used as substrates acetylated
peptides conjugated to a nonphysiological fluorophore. Later results showed, however, that the fluorophore
played an unexpected role that it should not have: no activity was found in
its absence of the fluorophore, i.e. with only the acetylated peptides in
the assays. Therefore
it was questioned whether the effects of these natural products were really
caused by direct affects on the sirtuin protein, and it was suggested that the
focus solely on sirtuins might be to narrow (Borra
et al., 2005;
Kaeberlein et al., 2005). A more recent publication confirmed the claim
that resveratrol is not a direct activator of SIRT1 enzyme activity (Beher
et al., 2009).
A publication in 2008 (Kahyo
et al., 2008) actually showed that the use of a different acetylated
peptide as SIRT1 substrate led to quite different results: in their assay
system, resveratrol and fisetin showed only marginal activation of SIRT1 (about
1.3-fold), and only piceatannol had a significant activating effect (about
3-fold). The other supposed activators actually behaved as inhibitors of
SIRT1: Butein, isoliquiritigenin, and quercetin reduced the activities to
0.04, 0.32, and 0.38-fold, respectively.
See also a
comment in the general page on Sirtuins:
more... , and remarks in the
page on sirtuin inhibitors (more...)
Synthetic sirtuin activators
The poor bioavailability of resveratrol, its rapid metabolization,
and its capacity to interact with multiple targets are not properties desirable
in a drug ('dirty' molecules for the pharmaceutical companies). Therefore it is of considerable interest to find other molecules with
the same effect, but higher bioavailabiltiy, specificity, and potency.
Several companies looked for that. One found several quinoxaline derivatives
havíng such effects (Nayagam
et al. 2006), but I will not go into detail here, because there are apparently
no detailed studies in animals yet.
Another company (Sirtris
Pharmaceuticals) is apparently much further. The screening identified a
number of promising compounds (Milne
et al., 2007), and some of them are shown in Fig. 2. In particular SRT1720 appeared to be 1000-fold more active than SRT501 (the resveratrol
formulation of the company) in in vitro assays, and the
experiments with mice also were quite successful. Recent work (Feige
et al., 2008;
et al., 2009) demonstrated that not only resveratrol, but also SRT1720
produced effects like calorie restricted diets. Modifications of the backbone
were also tested (Vu
et al., 2009), and novel SRT1 activators were published (Fig.
et al., 2009). Human trials are apparently already under way (October 2009),
and it will be exciting to see the outcome.
Synthetic SIRT1 activators.
Recently published novel SIRT1 activators (Bemis
et al., 2009)
I will not attempt to list and discuss all the publications dealing
with the many roles of sirtuins and the many effects observed with
resveratrol in cell-free systems, with tissue cultures, and in animal model
systems: that is just too much, and should be the privilege of more
Nevertheless, it is quite clear that there is pretty good evidence that resveratrol and
other compounds can mimic the effects of a low calorie diet. However, it is
also clear that there are some concerns that should be considered before taking
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The source for most of the information
summarized in this page
Alcain, F. J., Villalba, J. M., 2009a. Sirtuin
activators. Expert Opinion on Therapeutic Patents 19, 403-414.
Background: Sirtuin 1 - 7 (SIRT1 - 7) are deacetylases that are
dependent on NAD+ for their activity. SIRT1 down-regulates p53
activity, increasing lifespan, cell survival, and neuroprotection; it also
deacetylates peroxisome proliferator-activated receptor-gamma and its
coactivator 1α, promoting fat mobilization, increasing mitochondrial size
and number, and positively regulating insulin secretion. Sirtuins link
nutrient availability and energy metabolism. Calorie restriction, which
increases lifespan and is beneficial in age-related disorders, activates
sirtuin. Major efforts are thus focused to developing sirtuin activators.
Objective: After discussing the potential involvement of sirtuins in
pathophysiological processes, this review looks at new, synthetic sirtuin
Conclusions: To date, resveratrol is the most potent natural compound
able to activate SIRT1, mimicking the positive effect of calorie
restriction. Resveratrol might help in the treatment or prevention of
obesity and in preventing the aging-related decline in heart function and
neuronal loss. As resveratrol has low bioavailability and interacts with
multiple molecular targets, the development of new molecules with better
bioavailability and targeting sirtuin at lower concentrations is a promising
field of the medicinal chemistry. New SIRT1 activators that are up to 1000
times more effective than resveratrol have recently been identified. These
improve the response to insulin and increase the number and activity of
mitochondria in obese mice. Human trials with a formulation of resveratrol
with improved bioavailability and with a synthetic SIRT1 activator are in
(Note: In Fig. 3, the structures of fisetin and quercetin lack an
H-atom at the single bonded oxygen in the 3-position. Also, although it is formally
correct to call them flavones, in the nomenclature used by most plant
scientists they are called 'flavonols'
because of the -OH group in the 3-position. In Fig. 6, the three O-CH3
groups at the 'top' aromatic ring are missing in SRT1460).
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