rapamycin supplementation was initiated of
about 38% for females and 28% for males. In
an ongoing study, mice are being fed rapamy-
cin beginning at 270 days, with a significant
increase in survival also being apparent in this
Rapamycin was first identified as a natural
product of the bacterium Streptomyces hygro-
scopicus in soil samples from Easter Island —
famous for its impressive rock-carved human
statues (Fig. 1). The compound was selected for
inclusion in the ITP on the basis of its known
property as an inhibitor of the kinase enzyme,
target of rapamycin (TOR). TOR signalling has
previously been linked to the ageing process in
invertebrates2–6, but until now it had remained
an open question as to whether TOR signalling
also has a central role in mammalian ageing.
The findings of Harrison et al.1 make TOR the
first protein that has been shown to modulate
lifespan in each of the four model organisms
most commonly used to study ageing: yeast,
worms, flies and mice7.
How does TOR activity influence ageing?
Among other functions, TOR promotes
translation of messenger RNA into protein
by the ribosome, and inhibits a pathway that
degrades cellular products in lysosomal vesicles
(autophagy) — both of which have been impli-
cated in ageing in invertebrate species7. Regula-
tion of mRNA translation by TOR, in particular,
has emerged as a lifespan-determining pathway
that is highly conserved between yeast and the
nematode worm Caenorhabditis elegans. In
both species, mutations in targets of TOR, such
as ribosomal S6 kinase (an enzyme involved in
protein translation), several translation-initia-
tion factors and multiple ribosomal proteins,
increase lifespan8. In addition, TOR influences
cell growth, cell-cycle progression, mitochon-
drial metabolism and insulin-like signalling.
Untangling the relative contributions of each of
these processes to the lifespan extension in mice
conferred by rapamycin is likely to stimulate
much interest during the next few years.
TOR signalling has also received attention
for its role as a possible mediator of dietary
restriction. This is defined as a reduction in
nutrient availability without malnutrition, and
has long been known to increase lifespan in spe-
cies ranging from yeast to rodents7. TOR activ-
ity is reduced by dietary restriction, and genetic
studies in invertebrate models have linked the
inhibition of TOR to increased longevity by
dietary restriction7. For example, a recent study
in yeast showed that TOR inhibition increases
Anti-ageing drugs — compounds that slow
the hands of time and allow humans to live far
beyond their natural span — have long been
fertile ground for science-fiction writers. More
recently, however, the possibility that such com-
pounds might exist, and might perhaps even be
within reach, has gained scientific credibility. In
this issue (page 392), Harrison et al.1 provide
evidence that pharmacological intervention
in the ageing process is feasible in mammals*.
They report that dietary supplementation with
rapamycin — a compound known to be linked
to lifespan in invertebrates — significantly
increases the lifespan of mice.
The US National Institute on Aging’s Inter-
ventions Testing Program (ITP) was designed
to test compounds of interest for effects on
ageing in mice1. Anyone from the scientific
community can nominate a compound for
consideration by the ITP, and selected com-
pounds are tested in parallel longevity studies
at laboratories at three sites, providing built-in
triplicate replication and high statistical power.
Several compounds have already been tested.
Of these, rapamycin is the first to robustly
increase lifespan across all three centres and
in both male and female mice.
As is often the case in science, this study
benefited from a fortuitous accident. Early on,
the ITP researchers realized that simply adding
rapamycin to feed failed to maintain high levels
of the drug, so a specially formulated feed was
developed in which rapamycin is encapsulated
for timed release in the intestine. It took more
than a year to develop the special feed, which
meant that mice in the first cohort to receive
rapamycin were 600 days old when supplemen-
tation was initiated. As Harrison et al.1 note,
this is “roughly the equivalent of a 60-year-
old person”. Amazingly, both the median and
maximum lifespan of these middle-aged mice
were significantly increased by rapamycin
supplementation. For instance, rapamycin
increased maximum lifespan (defined by the
90th survival percentile) from 1,094 days to
1,245 days for female mice and from 1,078 days
to 1,179 days for male mice. This translates into
a striking increase in life expectancy at the time
*This article and the paper concerned1 were published online
on 8 July 2009.
A midlife longevity drug?
Matt Kaeberlein and Brian K. Kennedy
The small molecule rapamycin, already approved for clinical use for various human disorders, has been
found to significantly increase lifespan in mice. Is this a step towards an anti-ageing drug for people?
Figure 1 | Rapa Nui and rapamycin. Rapamycin, the compound shown by Harrison et al.1 to prolong
lifespan in mice, was first identified in soil samples taken on Easter Island, the Polynesian island famed
for its rock-carved figures. Rapamycin compounds are used clinically as immunosuppressants for organ
transplants, as a treatment for advanced kidney cancer, and to prevent narrowing of coronary arteries
after angioplasty. Easter Island is also known as Rapa Nui, from where rapamycin gets its name.
Vol 460|16 July 2009
NEWS & VIEWS
© 2009 Macmillan Publishers Limited. All rights reserved
the amounts of a nutritionally responsive tran-
scriptional activator Gcn4, and demonstrated
that this is required for full lifespan extension
from dietary restriction9. Similarly, autophagy
must be induced for lifespan to be extended by
dietary restriction in C. elegans10.
On the basis of these studies, it is tempting to
speculate that rapamycin may be functioning as
a dietary-restriction mimetic — a small mole-
cule that provides the benefits of dietary restric-
tion without requiring a reduction in food
intake. Like dietary restriction, TOR inhibi-
tion not only increases lifespan, but also confers
protection in invertebrate and rodent models
against age-associated disorders, including car-
diovascular dysfunction, diet-induced obesity
and cancer7. Cancer inhibition in particular is
a hallmark of dietary restriction in rodents, and
rapamycin analogues are already used clinically
as a treatment for certain forms of cancer.
Despite these links, Harrison et al.1 do not
strongly favour the idea that rapamycin is mim-
icking dietary restriction in mice. This is based
on their data that rapamycin extends lifespan
without reducing body weight, and when treat-
ment is initiated during middle age (late-life
onset of dietary restriction has shown incon-
sistent effects on longevity in previous studies).
It is worth pointing out, however, that a true
dietary-restriction mimetic may not reduce
body weight if it mimics the signalling events
(and downstream responses) associated with
dietary restriction without changing food con-
sumption. Also, dietary restriction has not yet
been extensively characterized in mice of the
genetically diverse background used by Har-
rison et al., so it is difficult to predict whether
dietary restriction in these animals would have
effects similar to rapamycin. Thus, although it
is premature to say for certain that rapamycin
is functioning as a dietary-restriction mimetic
in mice, the known role of TOR in the nutrient
response, and the genetic relationship between
TOR signalling and dietary restriction in inver-
tebrates, make this a reasonable possibility.
Is this the first step towards an anti-ageing
drug for people? Certainly, healthy individuals
should not consider taking rapamycin to slow
ageing — the potential immunosuppressive
effects of this compound alone are sufficient
to caution against this. On the basis of animal
models, however, it is interesting to consider
that rapamycin — or more sophisticated strate-
gies to inhibit TOR signalling — might prove
useful in combating many age-associated dis-
orders. Also, as relevant downstream targets of
TOR are better characterized, it may be possi-
ble to develop pharmacological strategies that
provide the health and longevity benefits with-
out unwanted side effects. So, although extend-
ing human lifespan with a pill remains the
purview of science-fiction writers for now, the
results of Harrison et al.1 provide a reason for
optimism that, even during middle age, there’s
still time to change the road you’re on.
Matt Kaeberlein and Brian K. Kennedy are in the
Departments of Pathology and Biochemistry,
University of Washington, Seattle, Washington
1. Harrison, D. E. et al. Nature 460, 392–395 (2009).
2. Jia, K., Chen, D. & Riddle, D. L. Development 131,
3. Kaeberlein, M. et al. Science 310, 1193–1196 (2005).
4. Kapahi, P. et al. Curr. Biol. 14, 885–890 (2004).
5. Powers, R. W. 3rd, Kaeberlein, M., Caldwell, S. D., Kennedy,
B. K. & Fields, S. Genes Dev. 20, 174–184 (2006).
6. Vellai, T. et al. Nature 426, 620 (2003).
7. Stanfel, M. N., Shamieh, L. S., Kaeberlein, M. & Kennedy,
B. K. Biochim. Biophys. Acta advance online publication
8. Smith, E. D. et al. Genome Res. 18, 564–570 (2008).
9. Steffen, K. K. et al. Cell 133, 292–302 (2008).
10. Hansen, M. et al. PLoS Genet. 4, e24 (2008).
Competing financial interests: declared (see online article
Striking correlations have been observed
between Earth’s cloud cover and the flux of
galactic cosmic rays entering our atmosphere.
The decrease in galactic cosmic ray (GCR)
flux by about 15% over much of the twentieth
century has led to the hypothesis that GCRs
could influence climate through their effect
on cloudiness. This controversial possibility
is revisited in a paper in Geophysical Research
Letters by Pierce and Adams1.
There are several plausible mechanisms that
could link GCR flux and cloud properties2. A
leading candidate is the ‘ion–aerosol clear-air
mechanism’, in which atmospheric ions cre-
ated by GCRs act as nuclei for the formation of
atmospheric particles. The nucleation of new
nanometre-sized aerosol particles is observed
frequently, and in many parts of the atmos-
phere, and is thought to be a major source of
cloud-condensation nuclei (CCN) — parti-
cles large enough for cloud droplets to form
around them. The link between GCRs and cli-
mate is therefore plausible because any change
in GCR-ionization rate might be expected to
drive changes in cloud-droplet concentrations,
and hence the amount of solar radiation that
clouds reflect back to space.
Atmospheric ions can indeed seed new par-
ticles3, but two outstanding questions have
hampered progress. What fraction of nuclei is
created this way? And what fraction of these
particles grows large enough to influence CCN?
To be relevant to recent climate change, it would
be necessary to show that the decrease in GCR
flux during the twentieth century could lead to
significant changes in CCN and clouds.
In their paper1, Pierce and Adams estimate the
magnitude of the ion–aerosol clear-air mecha-
nism. They used a global atmospheric model
with a detailed treatment of aerosol physics to
estimate some limiting values of CCN formation
from changes in GCR flux. Their conclusion is
clear: CCN concentrations just aren’t very sensi-
tive to the changes in GCRs that have occurred
during the twentieth century. The authors
predict that CCN concentrations will change
by less than 0.1% between solar maxima and
minima as GCRs change by 15% — about the
same as the change seen during the last century.
They estimate that this change in CCN trans-
lates into a change of 0.005 watts per square
metre in solar radiation reflected from clouds,
insignificant compared with the greenhouse-gas
warming of 2 watts per square metre or more
over roughly the same period.
Pierce and Adams’s model is quite sophis-
ticated in the way it treats the global lifecycle
of aerosols, from formation at nanometre sizes
to their eventual growth over days to weeks to
CCN sizes. But rather than trying to model the
complex ion–aerosol processes in detail (phys-
ics that is still incompletely understood), they
make an upper-limit assumption that all nucle-
ation is due to ions, thereby circumventing one
obstacle to making such a global assessment.
Is this negative result the last word on the ion–
aerosol clear-air mechanism? Climate modellers
are always quick to point out that predictions
can be model-dependent. Certainly CCN may
be more sensitive to the ion-induced nucleation
rate in a different model or under conditions not
explored by Pierce and Adams. But other global-
model studies4,5 of nucleation suggest that CCN
are fairly insensitive to the nucleation rate for a
simple reason: during the time taken for nuclei
to grow to CCN sizes, coagulation depletes
particle concentrations — just as raindrops
are always fewer in number than cloud drops.
Unless there is some as-yet-undiscovered pro-
cess that accelerates the growth of a few charged
nuclei all the way up to CCN sizes, this low sen-
sitivity is likely to be a robust conclusion.
Despite this result1, it is likely that a cosmic-
ray–cloud–climate connection will continue
to be explored, for two reasons. First, scien-
tists continue to be intrigued by correlations
between cosmic rays, Earth’s electrical state
and climate variables (clouds, precipitation,
drought and so on) on timescales from hours
to millennia6,7. Because the climate displays a
Cosmic rays, clouds and climate
Galactic cosmic rays could influence Earth’s cloudiness by creating aerosol
particles that prompt cloud formation. That possible effect looks to be
smaller than thought, but the story won’t end there.
NATURE|Vol 460|16 July 2009
NEWS & VIEWS
© 2009 Macmillan Publishers Limited. All rights reserved