is clearly a major driving force in the formation
of the rare encounter complexes described by
Tang and colleagues. Less studied, however,
is the role of short-range desolvation effects
— where the protein–protein interactions
force solvent molecules away from the pro-
teins — during and after collisions. It has been
suggested that hydrophobicity is involved
in reorientating the molecules to form the
final, productive complex5. Computational
simulations also show that desolvation energy
plays a part in orientating the encounter com-
plexes’ interacting subunits around the final,
specific complex state9.
Tang et al.2 describe structural features of
the encounter complexes (assuming that they
interact as rigid bodies), and their results are
consistent with the general idea of a funnel-
shaped binding-energy well that narrows as
the two proteins approach one another. This
implies that there are many possible routes for
arriving at the final complex at the bottom of
the energy well, and that these are determined
by transient interactions between the partners
in the encounter complexes, with the path-
ways converging as they get lower in energy
and closer to the final complex. Indeed, rigid-
body docking calculations based on optimiza-
tion of the binding energy of the interacting
molecules9–11 already describe a pool of alter-
native encounter complexes on the way to
forming the functional complex. Whether
these ensembles of orientations reflect the
true binding-energy landscape will depend
on the accuracy of the energy description of
these computer models and the efficiency
of the sampling method, an area of current
debate. Molecular-dynamics simulations
show that some encounter complexes could
be sufficiently long-lived for their side chains
to acquire a variety of conformational states,
some of which are similar to those in the final,
functional complex12. But it remains to be seen
how many of the minor species are true pro-
ductive encounter complexes, and which are
the preferred paths to the specific binding
mode of the final complex.
It is now apparent that rare encounter com-
plexes might control not only the kinetics of
the assembly process, but also the way the
complex is put together and hence its coop-
erativity. Furthermore, the population of non-
specific complexes can be restricted by the
order in which the different subunits are assem-
bled. Greater understanding of the route to
longer-term relationships between molecules
will no doubt emerge from integrating a wide
variety of experimental data with theoretically
sound computer modelling13,14 of their brief
Tom L. Blundell is in the Department of
Biochemistry, University of Cambridge,
Tennis Court Road, Cambridge CB2 1GA, UK.
Juan Fernández-Recio is at the Institute of
Biomedical Research, Barcelona Science Park,
Barcelona 08028, Spain.
1. Gavin, A. C. et al. Nature 415, 141–147 (2002).
2. Tang, C., Iwahara, J. & Clore, G. M. Nature 444, 383–386
3. Harmer, N. J. et al. Biophys. Chem. 100, 545–553 (2002).
4. Iwahara, J. & Clore, G. M. Nature 440, 1227–1230 (2006).
5. Crowley, P. B. & Ubbink, M. Acc. Chem. Res. 36, 723–730
6. Muresanu, L. et al. J. Biol. Chem. 281, 14503–14513 (2006).
7. Schreiber, G. & Fersht, A. R. Nature Struct. Biol. 3, 427–431
8. Gabdoulline, R. R. & Wade, R. C. Curr. Opin. Struct. Biol. 12,
9. Fernández-Recio, J., Totrov, M. & Abagyan, R. J. Mol. Biol.
335, 843–865 (2004).
10. Gray, J. J. et al. Proteins 52, 118–122 (2003).
11. Camacho, C. J. & Vajda, S. Proc. Natl Acad. Sci. USA 98,
12. Rajamani, D., Thiel, S., Vajda, S. & Camacho, C. J.
Proc. Natl Acad. Sci. USA 101, 11287–11292
13. de Bakker, P. I., Furnham, N., Blundell, T. L. & DePristo, M. A.
Curr. Opin. Struct. Biol. 16, 160–165 (2006).
14. Furnham, N., Blundell, T. L., DePristo, M. A. & Terwilliger,
T. C. Nature Struct. Mol. Biol. 13, 184–185 (2006).
Grapes versus gluttony
Matt Kaeberlein and Peter S. Rabinovitch
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 what-
ever they want, whenever they want, without
having to worry about the consequences. A
paper by Baur et al.1 on page 337 of this issue
suggests that guilt-free gluttony might not be
In this report, mice fed a diet akin to coco-
nut cream pie for every meal showed a strik-
ing increase in survival and health when their
chow was supplemented with resveratrol, a
poly phenolic 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 prob-
lems that plague humans who overindulge
at the dinner table, including obesity, insulin
resistance and heart disease. Baur et al. found
*This article and the paper concerned1 were published online
on 1 November 2006.
that although resveratrol did not prevent obes-
ity, 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, includ-
ing yeast, worms, flies, spiders and fish. Impor-
tantly, 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 fun-
damental level. The genetic pathways influ-
encing this phenomenon are currently
Grape expectations: The
Triumph of Bacchus, painted by
Cornelis de Vos (1584–1651).
MUSEO DEL PRADO, MADRID
NATURE|Vol 444|16 November 2006
NEWS & VIEWS
a hot topic of research and debate. Download full-text
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 ben-
eficial 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 res-
veratrol 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 particu-
lar enzymes (protein deacetylases) of the Sir2
family of proteins (sirtuins). Sirtuins are evo-
lutionarily conserved mediators of long evity
that might also play a role in lifespan exten-
sion 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 attrib-
uted to resveratrol in vivo8. However, there is
a surprising lack of biochemical evidence that
resveratrol directly increases sirtuin-mediated
deacetylation of biologically relevant sub-
strates, 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 resvera-
trol 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-restric-
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 Inter-
net 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 con-
trolled 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 dis-
ease. Even if resveratrol doesn’t make the grade,
it is not the last hope of gerontologists, or nec-
essarily even the best. Studies of several other
compounds are under way in multi centre stud-
ies of mouse ageing sponsored by the National
Institute on Aging11. These include potent
antioxidants and compounds targeting other
pathways thought to influence lifespan exten-
sion 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.
Matt Kaeberlein and Peter S. Rabinovitch are
in the Department of Pathology, University of
Washington, Seattle, Washington 98195, USA.
1. Baur, J. A. et al. Nature 444, 337–342 (2006).
2. Soleas, G. J., Diamandis, E. P. & Goldberg, D. M. Clin.
Biochem. 30, 91–113 (1997).
3. Howitz, K. T. et al. Nature 425, 191–196 (2003).
4. Longo, V. D. & Kennedy, B. K. Cell 126, 257–268
5. Kaeberlein, M. et al. J. Biol. Chem. 280, 17038–17045
6. Wood, J. G. et al. Nature 430, 686–689 (2004).
7. Valenzano, D. R. et al. Curr. Biol. 16, 296–300 (2006).
8. Baur, J. A. & Sinclair, D. A. Nature Rev. Drug Discov. 5,
9. Borra, M. T., Smith, B. C. & Denu, J. M. J. Biol. Chem. 280,
10. Zang, M. et al. Diabetes 55, 2180–2191 (2006).
Spinning discs in the lab
Steven A. Balbus
What causes gas to be drawn in towards black holes, rather than remain in a
stable orbit as planets do around the Sun? A laboratory result indicates that
something more than just hydrodynamics must be at work.
On page 343 of this issue, Ji et al.1 describe a
meticulous experiment in which they confined
water between two independently turning
cylinders. Through artful experimental design,
the authors were able to reduce viscous effects
in the resulting ‘Couette’ flow to a level of one
part in two million. They chose the veloci-
ties of the cylinders so that they would mimic
— and so compel the confined fluid to mimic
— so-called keplerian rotation, which is typi-
cal of astrophysical disks around black holes.
Here, velocity is inversely proportional to the
square-root of the distance from the centre of
The result was that nothing happened at all:
the fluid continued to rotate stably. But why
exactly do astrophysicists and fluid dynami-
cists find this apparently harmless result so
In the early 1970s, astrophysicists were strug-
gling with the exciting and controversial ques-
tion of whether black holes — objects whose
gravity is so great that nothing, not even light,
can escape once captured — were real2. Only
slightly earlier, a series of compact sources of
X-ray radiation had been discovered. One
model held that this radiation originated from
gas disks surrounding black holes in binary sys-
tems of close stars3 and galactic nuclei4. This gas
would dissipate its energy as heat, and ultimately
X-ray radiation. Its angular momentum would
be transported outward, and the gas would spi-
ral inward towards the hole. By understanding
these ‘accretion disks’, astronomers hoped that
they would, in one fell swoop, both explain the
mysterious X-ray sources and prove that black
The existence of black holes and their accre-
tion disks is now widely accepted by both
theorists and observers. But understanding
the dynamics of accretion disks, in black holes
and in other types of system, has turned out
to be an extremely knotty problem. Why do
disks accrete at all? Why does gas in motion
around a massive centre not remain in a stable,
The problem is that energy dissipation and
angular-momentum transport are properties
of a viscous fluid, and the viscosity of the disk
gas is far too small to account for the angular-
momentum loss that leads to accretion. This
problem might be solved if a keplerian gas
NATURE|Vol 444|16 November 2006
NEWS & VIEWS