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[A1CR]

The subject of this message stems from the painting shown in
paper (3).
And, maybe, the expectations are also the same for the
grape-wine-reveratrol-aholics. Gluttony galore. "But if
you must have a
Big Mac, fries and apple pie, we may soon know if you should
supersize that
resveratrol shake." The papers below (1-3) appear not to be
in our archives
and are availed. This is fun.

1. Check E.
A votre sante: now in pill form?
Nature. 2006 Nov 2;444(7115):11. No abstract available. News
PMID: 17080047 é

SUMMARY: 'Life-enhancing' effects of resveratrol cause a stir.

CONTEXT: David Sinclair believes resveratrol is a miracle
drug. He's been
taking it for three years because he hopes it will help him
live a healthier
life, despite a lack of evidence that it works in humans -
or any data on
the safety of long-term exposure.

But this week, Sinclair comes a step closer to proving that
he's on to
something. He and his colleagues report in a paper published
online in
Nature1 that this compound counteracts the ill effects of a
high-fat,
high-calorie diet - at least in mice. To some scientists,
the finding has
the whiff of a landmark discovery: it could lay the
foundations for a future
drug that blocks the toxic effects of obesity in humans. But
how solid is
that foundation?

The research is certainly striking. The study was led by
Sinclair, of
Harvard Medical School in Cambridge, Massachusetts, and
Rafael de Cabo of
the National Institute on Aging in Baltimore, Maryland.
Their team divided
one-year-old mice into three groups. One group ate regular
food. Another ate
high-calorie food. The third group ate the high-calorie diet
along with a
daily dose of resveratrol, a chemical found in many plant
species, including
red grapes - and thus also red wine.

After six months, all the mice fed high-calorie diets had
grown fat. But
after a year the mice in the resveratrol group seemed a lot
healthier than
their high-calorie-fed counterparts. The drug seemed to
prevent these mice
from developing a diabetes-like illness and liver damage,
and reduced their
risk of death by 30%, compared with the mice on high-calorie
diets that did
not get the drug.

That's a potentially revolutionary finding. But for those
desperate to undo
the effects of years of overeating, it is a far cry from a
human cure.
First, the study doesn't attempt to show whether resveratrol
reverses the
damage caused by the toxic diet, as the mice were on the
drug when they
started the diet. The equivalent experiment would be to feed
a human a
relatively healthy diet until middle age, and then force him
or her to binge
on Big Macs and resveratrol simultaneously.

Second, there is a dearth of data on how resveratrol works
in mice - and no
evidence that it works at all in humans. Sinclair believes
that it triggers
the same pathways as those activated by calorie-restriction
diets, which
have been shown to increase lifespan in some animals (but
not in humans,
yet). He hypothesizes that resveratrol works through
proteins called
sirtuins. But although there are data to prove this in
yeast, worms and
fruitflies, no analogous data have proved it for humans or
mice - despite
tantalizing hints. So it is hard to know how well
resveratrol's benefits
will apply in people.

A third caveat is that mice on resveratrol didn't exactly
mimic people on
calorie-restriction diets. The mice stayed fat, for
instance, and their
cholesterol levels were far higher than those of mice on the
standard diet.
This means either that Sinclair and de Cabo decoupled
obesity from its
downstream ill-health effects or that resveratrol doesn't
really mimic
calorie restriction in mammals. Of course, the mechanism
isn't so important
if the drug works. But it means that, for now, experts are
cautioning
against the idea of rushing to an Internet pharmacy to buy
resveratrol2. It
is a dicey idea to take lifelong doses of a drug without
having a clue about
its mechanism of action or its long-term effects on the body.

Finally, although the study itself is robust as published,
the analysis
involves only 121 mice, many of which are still alive - the
experiment isn't
truly over until all the mice have died. Further studies by
the same group
will look at whether resveratrol extends lifespan in the
healthy mice, too.
Until all these results are in, we don't really have a
complete picture of
the drug's effects in obese and normal mice.

Even so, Sinclair is forging ahead to answer some of these
questions. He is
a co-founder of Cambridge-based Sirtris Pharmaceuticals,
which aims to
develop drugs that act on sirtuins. This summer, Sirtris
tested a modified
version of resveratrol in 85 healthy men. The company said
on 4 October that
it saw no ill effects of the drug in these volunteers, so it
has now begun a
clinical trial in 90 patients with diabetes.

References

2. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C,
Kalra A, Prabhu VV,
Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S,
Becker KG, Boss O,
Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG,
Lakatta EG, Le
Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de
Cabo R, Sinclair
DA.
Resveratrol improves health and survival of mice on a
high-calorie diet.
Nature. 2006 Nov 1; [Epub ahead of print]
PMID: 17086191

SUMMARY: Resveratrol (3,5,4'-trihydroxystilbene) extends the
lifespan of
diverse species including Saccharomyces cerevisiae,
Caenorhabditis elegans
and Drosophila melanogaster. In these organisms, lifespan
extension is
dependent on ...

CONTEXT: ...to identify 25 that enhance SIRT1 activity in
vitro.
Resveratrol, a molecule produced by a variety of plants in
response to
stress, emerged as the most potent. Resveratrol has since
been shown to
extend the lifespan of evolutionarily...

Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan
of diverse
species including Saccharomyces cerevisiae, Caenorhabditis
elegans and
Drosophila melanogaster. In these organisms, lifespan
extension is dependent
on Sir2, a conserved deacetylase proposed to underlie the
beneficial effects
of caloric restriction. Here we show that resveratrol shifts
the physiology
of middle-aged mice on a high-calorie diet towards that of
mice on a
standard diet and significantly increases their survival.
Resveratrol
produces changes associated with longer lifespan, including
increased
insulin sensitivity, reduced insulin-like growth factor-1
(IGF-I) levels,
increased AMP-activated protein kinase (AMPK) and peroxisome
proliferator-activated receptor- coactivator 1 (PGC-1)
activity, increased
mitochondrial number, and improved motor function.
Parametric analysis of
gene set enrichment revealed that resveratrol opposed the
effects of the
high-calorie diet in 144 out of 153 significantly altered
pathways. These
data show that improving general health in mammals using
small molecules is
an attainable goal, and point to new approaches for treating
obesity-related
disorders and diseases of ageing.

The number of overweight individuals worldwide has reached
2.1 billion,
leading to an explosion of obesity-related health problems
associated with
increased morbidity and mortality1, 2. Although the
association of obesity
with increased risk of cardiovascular disease and diabetes
is well known, it
is often under-appreciated that the risks of other
age-related diseases,
such as cancer and inflammatory disorders, are also
increased. At the other
end of the spectrum, reducing caloric intake by 40% below
that of ad
libitum-fed animals (caloric restriction) is the most robust
and
reproducible way to delay age-related diseases and extend
lifespan in
mammals3, 4.

Experiments with Saccharomyces cerevisiae and Drosophila
melanogaster have
implicated the sirtuin/Sir2 family of NAD+-dependent
deacetylases and
mono-ADP-ribosyltransferases as mediators of the
physiological effects of
caloric restriction5. In mammals, seven sirtuin genes have
been identified
(SIRT1-7). SIRT1 regulates such processes as glucose and
insulin production,
fat metabolism, and cell survival, leading to speculation
that sirtuins
might mediate effects of caloric restriction in mammals5. We
previously
screened over 20,000 molecules to identify 25 that enhance
SIRT1 activity in
vitro6. Resveratrol, a molecule produced by a variety of
plants in response
to stress, emerged as the most potent.

Resveratrol has since been shown to extend the lifespan of
evolutionarily
distant species including S. cerevisiae, C. elegans and D.
melanogaster in a
Sir2-dependent manner6, 7, 8, 9. A recent study found that
resveratrol
improves health and extends maximum lifespan by 59% in a
vertebrate fish10.
In mammalian cells, resveratrol produces SIRT1-dependent
effects that are
consistent with improved cellular function and organismal
health11, 12, 13,
14, 15. Whether resveratrol acts directly or indirectly
through Sir2 in vivo
is currently a subject of debate16.

On the basis of the unprecedented ability of resveratrol to
improve health
and extend lifespan in simple organisms, we have asked
whether it has
similar effects in mice. We hypothesized that resveratrol
might shift the
physiology of mice on a high-calorie diet towards that of
mice on a standard
diet and provide the associated health benefits without the
mice having to
reduce calorie intake. Cohorts of middle-aged (one-year-old)
male C57BL/6NIA
mice were provided with either a standard diet (SD) or an
otherwise
equivalent high-calorie diet (60% of calories from fat, HC)
for the
remainder of their lives. To each of the diets, we added
resveratrol at two
concentrations that provided an average of 5.2 0.1 and 22.4
0.4 mg kg-1
day-1, which are feasible daily doses for humans. After 6
months of
treatment, there was a clear trend towards increased
survival and insulin
sensitivity. Because the effects were more prominent in the
higher dose
(22.4 0.4 mg kg-1 day-1, HCR), we initially focused our
resources on this
group and present the results of those analyses herein.
Analyses of the
other groups will be presented at a later date.

Increased survival

Mice on the HC diet steadily gained weight until 75 weeks of
age, after
which average weight slowly declined (Fig. 1a). Although
mice on the HCR
diet were slightly lighter than the HC mice during the
initial months, there
was no significant weight difference between the groups from
18-24 months,
when most of our analyses were performed. There was also no
difference in
body temperature (Table 1), food consumption (Supplementary
Fig. 1a, b),
total faecal output or lipid content (Supplementary Fig. 1c,
d), or
post-mortem body fat distribution (Supplementary Fig. 2).

Table 1: Effects of a high-fat diet and resveratrol on
various biomarkers in
plasma
=======================================================
Parameter Standard diet High calorie High calorie +
resveratrol Fed or
fasted
=======================================================
Free fatty acids (mequiv.)
0.27 (0.04) 0.59 (0.06)^§ 0.53 (0.03)^§ Fed
0.83 (0.10) 0.45 (0.20) 0.54 (0.05) Fasted
Triglycerides (mg/dl) 76.6 (6.8) 81.4 (6.6) 88.2 (10.8) Fasted
Cholesterol (mg/dl) 135 (7) 183 (20)^§ 204 (16)^§ Fasted
Insulin (ng/ml)
1.77 (0.64) 9.21 (1.95)^§ 2.46 (0.47)^§* Fed
0.73 (0.14) 2.70 (0.36)^§ 1.06 (0.30)^* Fasted
Glucose (mg/dl)
129.0 (5.4) 118.3 (4.7) 114.8 (6.3) Fed
94.5 (3.3) 125.3 (11.6)^§ 85.6 (10.3)^* Fasted
IGF-I (ng/ml)
346 (40) 534 (12)^§ 482 (21)^# Fed
625 (33) 999 (102)^§ 929 (81)^§ Fasted
IGFBP-1 (AU)
1.0 (0.3) 1.7 (0.3) 1.7 (1.0) Fed
1.0 (0.2) 0.5 (0.3) 0.3 (0.1)^§ Fasted
IGFBP-2 (AU) 1.0 (0.2) 0.7 (0.04) 0.9 (0.1) Fasted
Leptin (ng/ml) 2.0 (1.1) 21.6 (7.2) 11.6 (6.5) Fasted
Adiponectin (mg/ml1) 12.1 (1.6) 9.5 (0.5) 9.0 (0.8) Fed
Amylase (U/l) 2,060 (150) 2,960 (320)^§ 2,190 (230)^* Fasted
Ala aminotransferase (U/l) 347 (119) 390 (61) 446 (88) Fasted
Asp aminotransferase (U/l) 448 (85) 425 (90) 512 (46) Fasted
Creatine phosphokinase (U/l) 4,260 (1820) 2,010 (810) 2,520
(680) Fasted
Lactate dehydrogenase (U/l) 1,530 (240) 1,610 (170) 2,020
(180) Fasted
Alkaline phosphatase (U/l) 43.8 (3.4) 44.6 (6.0) 34.2 (1.4)
Fasted
Bilirubin (mg/dl) 0.16 (0.02) 0.10 (0.03) 0.16 (0.02) Fasted
Albumin (g/dl) 2.78 (0.16) 2.88 (0.19) 2.66 (0.14) Fasted
Creatinine (mg/dl) 0.54 (0.02) 0.48 (0.04) 0.46 (0.04) Fasted
Cyclo-oxygenase (liver, AU/mg) 1.00 (0.14) 0.80 (0.11) 0.83
(0.11) Fed
Citrate synthase (°C) 34.71 (0.14) 35.52 (0.17)^§ 35.57 (0.15)^§
=======================================================
Values shown are mean (s.e.m.).
AU, arbitrary units; U/l, units per litre.
^* P < 0.05 versus high calorie.
^§ P < 0.05 versus standard diet.
^# P,0.05 versus high calorie by one-tailed Student's
t-test.

At 60 weeks of age, the survival curves of the HC and HCR
groups began to
diverge and have remained separated by a 3-4-month interval
(Fig. 1b). A
similar effect on survival was observed in a previous study
of one-year-old
C57BL/6 mice on caloric restriction, ultimately resulting in
a 20% extension
of mean lifespan17. With the present age of the colony at
114 weeks, 58% of
the HC control animals have died (median lifespan 108
weeks), as compared to
42% of the HCR group and 42% of the SD controls. Although we
cannot yet
confidently predict the ultimate mean lifespan extension,
Cox proportional
hazards regression shows that resveratrol reduced the risk
of death from the
HC diet by 31% (hazard ratio = 0.69, P = 0.020), to a point
where it was not
significantly different from the SD group (hazard ratio =
1.03, P = 0.88).

Although resveratrol increased survival, it was important to
ascertain
whether quality of life was maintained. One way to assess
this was to
measure balance and motor coordination, which we did by
examining the
ability to perform on a rotarod. Surprisingly, the
resveratrol-fed HC mice
steadily improved their motor skills as they aged, to the
point where they
were indistinguishable from the SD group (Fig. 1c). It is
possible that the
improved rotarod performance might have been due to minor
differences in
body weight but we view this as unlikely because we found no
correlation
between body weight and performance within groups and
rotarod performance
was also improved for resveratrol-treated SD mice (R.deC.
and K.P.,
unpublished data). These data are reminiscent of the
resveratrol-mediated
increase in motor activity in older individuals of the
vertebrate fish
species Nothobranchius furzeri10.

Increased insulin sensitivity

In humans, high-calorie diets cause numerous pathological
conditions
including increased glucose and insulin levels leading to
diabetes,
cardiovascular disease and non-alcoholic fatty liver
disease, a condition
for which there is no effective treatment18. The HC-fed mice
had alterations
in plasma levels of markers that predict the onset of
diabetes and a shorter
lifespan, including increased levels of insulin, glucose and
IGF-1 (Table
1). The HCR group had significantly lower levels of these
markers,
paralleling the SD group. An oral glucose tolerance test
indicated that the
insulin sensitivity of the resveratrol-treated mice was
considerably higher
than controls (Fig. 2a-d). Homeostatic model assessment,
which is used to
quantify insulin resistance, gave scores of 2.5 for SD, 8.8
for HC and 3.5
for HCR, confirming improved sensitivity (HCR versus HC, P =
0.01). Although
the persistence of high glucose levels for more than 60 min
following an
oral dose is unusual for young mice, it is typical for older
animals19.
Compared to the HC controls, the areas under the curves for
both glucose and
insulin levels were significantly decreased in the
resveratrol-fed HC group
and were not significantly different from mice in the SD
group (Fig. 2b, d).

Next, we investigated possible mechanisms behind these
metabolic effects.
AMPK is a metabolic regulator that promotes insulin
sensitivity and fatty
acid oxidation. Its activity correlates tightly with
phosphorylation at Thr
172 (p-AMPK). Chronic activation of AMPK occurs on a
calorically restriction
diet and has been proposed as a longevity strategy for
mammals20. Consistent
with this idea, additional copies of the AMPK gene are
sufficient to extend
lifespan in C. elegans21. Because we and others22 have
observed that
resveratrol can activate AMPK in cultured cells through an
indirect
mechanism (Fig. 2e; see also Supplementary 3a-d), we
examined whether AMPK
activation occurred in the livers of the resveratrol-fed
group. Resveratrol
showed a strong tendency towards inducing phosphorylation of
AMPK (Fig. 2f),
as well as two downstream indicators of activity, namely
phosphorylation of
acetyl-coA carboxylase at Ser 79 and decreased expression of
fatty acid
synthase (Supplementary Fig. 3e, f).

Decreased organ pathology

At 18 months of age it was apparent that the high-calorie
diet greatly
increased the size and weight of livers and that resveratrol
prevented these
changes (Fig. 3a-c; see also Supplementary Fig. 4a, b)
without altering
plasma lipid levels (Table 1). Histological examination of
liver sections by
staining with haematoxylin and eosin or oil red O revealed a
loss of
cellular integrity and the accumulation of large lipid
droplets in the
livers of the HC but not the HCR group. Blinded scoring of
the liver
sections for overall pathology on a scale of 0-4 (with 4
being the most
severe) gave mean values of 1.3 for the SD group, 2.8 for
the HC group and
0.8 for the HCR group (Fig. 3b). Plasma amylase, which can
indicate
pancreatic damage, was elevated in the HC group and was
significantly
reduced by resveratrol (Table 1). The reasons for the
elevation of plasma
amylase levels in the HC group are unclear given that
pancreatic sections of
all animals revealed no damage to the pancreas or decrease
in islet area
(data not shown). Differences in the weights of other organs
did not reach
statistical significance.

The ability of resveratrol to improve motor function and
increase insulin
sensitivity indicated that its effects were not confined to
the liver. To
test directly whether other organs also benefited, we
examined heart tissue
of the SD, HC and HCR mice. Blinded scoring of overall
pathology-taking into
account subtle changes in the abundance of fatty lesions,
cardiac muscle
vacuolization, degeneration and inflammation-on a relative
scale of 0-4
(with 4 being the most severe) gave mean values of 1.6 for
the SD group, 3.2
for the HC group and 1.2 for HCR group (Fig. 3d; see also
Supplementary Fig.
4c). Improvements in the morphology of the aortic elastic
lamina were also
apparent (Supplementary Fig. 4d).

Increased mitochondria

Exercise and reduced caloric intake increase hepatic
mitochondrial number23,
24 and we wondered whether resveratrol might produce the
same effect. The
livers of the resveratrol-treated mice had considerably more
mitochondria
than those of HC controls and were not significantly
different compared to
those of the SD group (Fig. 3e, f). There was also a trend
towards higher
citrate synthase activity in the resveratrol-fed mice (an
indicator of
increased mitochondrial content) although the effect was not
significant
(Table 1). Culturing FaO hepatoma or HeLa cells in the
presence of
resveratrol increased mitochondrial number (Fig. 3g, h),
similar to the
previously reported effect of culturing cells in serum from
calorically
restricted rats24.

Mitochondrial biogenesis in liver and muscle is controlled,
in large part,
by the transcriptional coactivator PGC-125, 26, the activity
of which, in
turn, is positively regulated by SIRT1-mediated
deacetylation27, 28. Hence,
the acetylation status of PGC-1 is considered a marker of
SIRT1 activity in
vivo27. Because this assay required more tissue than was
available, we
examined a separate cohort of one-year-old mice on the HC
diet that had been
treated with resveratrol for 6 weeks at 186 mg kg-1 d-1. The
acetylation
status of PGC-1 in the resveratrol-fed mice was threefold
lower than the
diet-matched controls (Fig. 3i, j). There was no detectable
increase in
SIRT1 protein levels in resveratrol-treated mice (data not
shown),
suggesting that SIRT1 enzymatic activity was enhanced by
resveratrol.

Microarrays and pathway analysis

These data demonstrate that resveratrol can alleviate the
negative impact of
a high-calorie diet on overall health and lifespan. To
determine to what
extent resveratrol had shifted the physiology of the
high-calorie group
towards the lower calorie group, we performed whole-genome
microarrays and
pathway analysis on liver samples. Z ratios were calculated
as described
previously29 and a subset of expression changes was verified
by polymerase
chain reaction with reverse transcription (RT-PCR)
(Supplementary Fig. 5).
In the HCR group, expression patterns for 782 out of 41,534
(<2%) individual
genes changed significantly relative to the diet-matched
controls (Fig. 4a,
b). Notably, within the top 12 most highly elevated
transcripts were serum
amyloid proteins (Saa1-3), major urinary proteins (Mup1 and
Mup3), and both
forms of hydroxysteroid dehydrogenase that degrade
testosterone (Hsd3b4,
Hsd3b5). The list of 12 most highly downregulated
transcripts included three
cytochrome p450 enzymes (Cyp2a4, Cyp2a5 and Cyp2b9) that are
known to
activate pro-carcinogens30. The complete data set is
available at
http://www.grc.nia.nih.gov/branches/rrb/dna/index/dnapubs.htm#2.

We next performed parametric analysis of gene set enrichment
(PAGE), a
computational method that determines differences between
pathways using a
priori defined gene sets31, 32. PAGE analysis indicated that
resveratrol
caused a significant alteration in 127 pathways, including
the TCA cycle,
glycolysis, the classic and alternative complement pathways,
butanoate and
propanoate metabolism, sterol biosynthesis and Stat3 signalling
(Supplementary Fig. 6; for a complete list see Supplementary
Fig. 7). Some
of the most highly downregulated pathways in the
resveratrol-fed group are
known to extend lifespan in model organisms when attenuated,
including
insulin signalling, IGF-1 and mTOR signalling, oxidative
phosphorylation and
electron transport33, 34, 35, 36. Downregulation of
glycolysis is a well
known marker of caloric restriction37 and has been proposed
as a mechanism
by which caloric restriction works38. The increase in Stat3,
a transcription
factor involved in cell survival and liver regeneration39,
is of note
because its activity is known to be suppressed in the liver
by high caloric
diets and shows an age-related decline in activity that is
attenuated by
caloric restriction40, 41.

A few of the pathway changes were unanticipated. Although we
had observed an
increase in mitochondrial number in the HCR group, there was
a decrease in
the transcription of numerous mitochondrial genes,
suggesting that the
turnover of mitochondrial proteins was reduced. This result
was unexpected,
but is consistent with a previous report showing that
SIRT1-dependent
activation of PGC-1 does not enhance transcription of
mitochondrial genes27.
Upregulation of complement, which occurs in obese and aged
mice, was also
observed in the HCR group for reasons that are currently
unclear.

It is notable that resveratrol opposed the effects of high
caloric intake in
144 out of 153 significantly altered pathways (Fig. 4c). In
fact, the PAGE
signature of the HCR group was considerably more similar to
that of the SD
group than the HC controls. Principal component analysis
yielded values
of -1.82 (SD), -1.41 (HCR) and 3.22 (HC), with 88.4% of the
variability
assigned to the first principal component, making the HC
group the clear
outlier (Fig. 4d).

We next compared our PAGE results to a pre-existing caloric
restriction data
set for C57BL/6 mice known as AGEMAP, hypothesizing that the
comparison of
changes induced by these two paradigms might reveal pathways
common to the
enhancement of health and longevity. Of the 36 different
pathways identified
by AGEMAP as being significantly altered by caloric
restriction, there was
sufficient overlap to compare 19 of them to our data (Fig.
4e). Pathways
altered in the same direction by caloric restriction and
resveratrol
included the downregulation of IGF-1 and mTOR signalling,
downregulation of
glycolysis, and upregulation of Stat3 signalling. One
interesting difference
was that cell cycle checkpoint and apoptotic pathways were
elevated in the
caloric restriction group but downregulated by resveratrol.
We do not favour
the interpretation that the resveratrol-treated livers were
undergoing less
apoptosis because levels of AST and ALT, two indicators of
hepatic
apoptosis, were unchanged (see Table 1). Perhaps the
downregulation of cell
cycle checkpoints is linked to the recent discovery that
inhibition of
checkpoint function in C. elegans increases stress
resistance and
lifespan42. Although the statistical power of this analysis
is limited by
the overlap in data sets, the results suggest that more
comprehensive
comparisons of the effects of resveratrol and caloric
restriction are
warranted.

Discussion

The ability of resveratrol to prevent the deleterious
effects of excess
caloric intake and modulate known longevity pathways
suggests that
resveratrol and molecules with similar properties might be
valuable tools in
the search for key regulators of energy balance, health and
longevity. As a
case in point, the most highly upregulated gene in the HC
group and second
most highly downregulated gene in the HCR group was Cidea,
which regulates
energy balance in brown fat and provides resistance to
obesity and diabetes
when knocked out43.

Taken together, the findings in this study show that
resveratrol shifts the
physiology of mice consuming excess calories towards that of
mice on a
standard diet, modulates known longevity pathways, and
improves health, as
indicated by a variety of measures including survival, motor
function,
insulin sensitivity, organ pathology, PGC-1 activity, and
mitochondrial
number. Notably, all these changes occurred without a
significant reduction
in body weight. Whether these effects are due to resveratrol
working
primarily through SIRT1, which is the case for simpler
metazoans, or through
a combination of interactions, as predicted by the
xenohormesis hypothesis6,
44, remains to be determined. In either case, this study
shows that an
orally available small molecule at doses achievable in
humans can safely
reduce many of the negative consequences of excess caloric
intake, with an
overall improvement in health and survival.

... one-year-old male C57BL/6NIA mice were maintained on
AIN-93G standard
diet (SD), AIN-93G modified to provide 60% of calories from
fat (HC), or HC
diet with the addition of 0.04% resveratrol (HCR). ...

3. Kaeberlein M, Rabinovitch PS.
Medicine: Grapes versus gluttony.
Nature. 2006 Nov 1; [Epub ahead of print] No abstract available.
PMID: 17086197

SUMMARY: A compound found in red grapes called resveratrol
improves the
health and lifespan of mice on a high calorie diet. This is
potentially good
news

CONTEXT: ...about the consequences. A paper by Baur et al.,
published today
on Nature's website, suggests that guilt-free gluttony might
not be a
fantasy. In this report, mice fed a diet akin to coconut
cream pie for every
meal showed a striking...

A compound found in red grapes called resveratrol improves
the health and
lifespan of mice on a high calorie diet. This is potentially
good news for
overweight humans. Does it bode well for the rest of us too?

Bacchus (Dionysus to the Greeks) has been long out of style,
but may be
granting new favours - particularly if you long to be one of
those people
who can seemingly eat whatever they want, whenever they
want, without having
to worry about the consequences. A paper by Baur et al.1,
published today on
Nature's website, suggests that guilt-free gluttony might
not be a fantasy.

Picture legend: MUSEO DEL PRADO, MADRID Grape expectations:
The Triumph of
Bacchus, painted by Cornelis de Vos (1584-1651).

In this report, mice fed a diet akin to coconut cream pie
for every meal
showed a striking increase in survival and health when their
chow was
supplemented with resveratrol, a polyphenolic compound found
in red grapes
or wine. Compared with animals fed a more standard diet,
mice fed the
high-calorie (60% from fat) diet without resveratrol had a
shorter lifespan.
They also showed many of the problems that plague humans who
overindulge at
the dinner table, including obesity, insulin resistance and
heart disease.
Baur et al. found that although resveratrol did not prevent
obesity, it did
prevent obesity-associated disease, at least in one strain
of mouse, and
conferred a nearly normal lifespan on these mice.

With the present epidemic of obesity in some Western
societies, this could
be very good news. But might resveratrol improve health or
lifespan beyond
that achieved with a healthy diet? The link between diet and
longevity has
been known to gerontologists since the discovery in the
1930s that reduced
caloric intake can increase the lifespan of rodents by up to
50%. Dietary
restriction has since been observed to have a similar effect
on longevity in
many different organisms, including yeast, worms, flies,
spiders and fish.
Importantly, dietary restriction not only increases
lifespan, but it also
delays the onset of nearly all age-associated diseases. For
this reason,
most gerontologists believe that dietary restriction affects
the intrinsic
ageing process at a fundamental level. The genetic pathways
influencing this
phenomenon are currently a hot topic of research and debate.

Like dietary restriction, resveratrol has long been known to
have
interesting properties. During the 1990s it was extensively
studied as a
potential link between improvements in a variety of health
indicators and
moderate consumption of red wine2. The antioxidant
properties of
resveratrol, in particular, have been suggested to account
for many of its
beneficial properties, including putative cardio-protective
and anticancer
activities, as well as providing protection against liver
failure. Here it
is noteworthy that Baur et al.1 show that resveratrol has a
profound ability
to prevent liver damage associated with the high-fat diet.

Resveratrol became of particular interest to gerontologists
with the report3
that it can increase lifespan in yeast by activating
particular enzymes
(protein deacetylases) of the Sir2 family of proteins
(sirtuins). Sirtuins
are evolutionarily conserved mediators of longevity that
might also play a
role in lifespan extension through dietary restriction4.
Although the
results from the initial study of resveratrol in yeast remain
controversial5, subsequent work has suggested that
resveratrol has modest
effects on lifespan in both worms and flies6, and a more
substantial effect
on lifespan in a short-lived fish7. Based on these findings,
it has been
proposed that resveratrol increases lifespan in several
different organisms
by a mechanism similar to dietary restriction8.

Baur et al.1 favour the view that many (perhaps all) of the
beneficial
properties of resveratrol are the result of increased
sirtuin activity, and
various studies have supported the idea that sirtuins
underlie the effects
attributed to resveratrol in vivo8. However, there is a
surprising lack of
biochemical evidence that resveratrol directly increases
sirtuin-mediated
deacetylation of biologically relevant substrates, and some
evidence that it
may not5, 9. Resveratrol is also known to interact with
numerous proteins
and pathways, including mitochondrial ATP synthase and
complex III,
fatty-acid synthase, protein kinase C, p53, MEK1, TNF- and
NF-B, all of
which are candidates for mediating its in vivo effects. In
particular,
activation of AMP kinase by resveratrol protects against
atherosclerosis and
liver damage in diabetic mice10, suggesting a likely
mechanism for the
observations reported by Baur and colleagues.

Given the available data, it is difficult to predict the
answers to a few
key questions. Will resveratrol have an effect on health and
longevity in
mice fed a standard diet, rather than a high-calorie diet?
Will it be
effective in mice with genetic backgrounds other than the
inbred strain used
in the current report? Will it be effective in humans?
Studies addressing
these questions are under way: the answers will go some way
towards
determining whether or not resveratrol is a bona fide
dietary-restriction
mimetic.

Many people will wonder whether they should start
supplementing their diets
with resveratrol. After all, it is generally regarded as
safe, and can be
purchased over the Internet with promises of improved health
and longevity.
Our advice is to exercise caution. The safety of resveratrol
at the high
doses in humans comparable to those used by Baur et al.1 is
unknown,
especially over the course of years or even decades, when
relatively modest
side effects could have dramatic consequences. A logical
next step would be
to initiate controlled studies to find out whether
resveratrol can safely
reduce the ill-effects associated with diabetes or obesity
in humans.

In the most optimistic assessment, a true mimetic of dietary
restriction
could be effective against many age-associated human
diseases, including
heart disease, diabetes, cancer and neurological disorders
such as
Alzheimer's disease. Even if resveratrol doesn't make the
grade, it is not
the last hope of gerontologists, or necessarily even the
best. Studies of
several other compounds are under way in multicentre studies
of mouse ageing
sponsored by the National Institute on Aging11. These
include potent
antioxidants and compounds targeting other pathways thought
to influence
lifespan extension through dietary restriction.

For now, we counsel patience. Just sit back and relax with a
glass of red
wine - which, alas, has only 0.3% of the relative
resveratrol dose given to
the gluttonous mice (note also that increasing the dose via
wine will not be
healthy). But if you must have a Big Mac, fries and apple
pie, we may soon
know if you should supersize that resveratrol shake.