NEWS & VIEWS RESEARCH

of senescence-associated secreted factors,

including IL-6 and matrix metalloproteinase
enzymes.
These results suggest that continuous
clearance of p16Ink4a-positive senescent cells
suspends the p16 Ink4a-dependent traits of
premature ageing that are due to BubR1 deficiency. However, it would be more appealing
if the ablation of senescent cells delayed features of ageing after the animals had begun
to develop senescent traits. To see whether
this was achievable, Baker et al. eliminated
senescent cells in a group of five-month-old
mice when traits of ageing were evident.
Another five months later, the mice showed
increased muscle-fibre diameter and improved
fitness performance compared with control
mice. They also had enlarged fat deposits and
decreased levels of senescence markers. So the
removal of p16Ink4a-positive cells also seems to
be beneficial even later in life.
Baker and colleagues elegant work is a
proof-of-concept for the premise that therapeutic elimination of senescent cells may
delay ageing-associated processes. Among
the questions that therefore arise are whether
these findings can be extrapolated to natural
ageing, and whether the observed functional
improvements are due to termination of
further damage or damage reversal.
For therapeutic purposes, regulating the
effects of senescent cells, rather than their
abundance, may be more manageable. Of relevance to this is the large number of factors that
are secreted by senescent cells. Some of these
reinforce senescence in their cell of origin,
whereas others affect nearby and even distant
cells, disrupting vital processes such as tissue
function and regeneration6,7 (Fig.1). So identifying the factors that are secreted by senescent
cells and contribute to ageing is a priority.
Deficiency of p16Ink4a ameliorates traits of
premature ageing, but does not completely
prevent them or extend lifespan3,10. Consistent with this, Baker et al. showed that features
of ageing that are independent of p16Ink4a
remain unchanged3, supporting the notion
that additional factors contribute to premature ageing. Investigations are therefore
needed into whether such factors are directly
involved in senescence, or instead are effector molecules of BubR1 function (such as the
anaphase-promoting complex).
This paper3 may also provide a clue to why
some organisms live longer than others. A provocative thought is that long-lived organisms
may be equipped with an immune system that
is better at eradicating senescent cells. Such
communication between senescent cells and
cells mediating immune surveillance is not
unprecedented. In mouse liver, for example,
injury to one cell type, hepatocytes, activates
another cell type, hepatic stellate cells. The
latter cells cause not only fibrosis but also
senescence, thereby attracting the natural
killer cells of the immune system to bring about

their own eventual demise and so limiting the

damage11. In humans, however, spontaneous
clearance of cells that express p16Ink4a abundantly is probably uncommon. As p16Ink4a is
often induced in precancerous lesions and even
in tumours, eliminating p16Ink4a-positive cells
may come with benefits that go beyond ageing.
It was recently shown12 that reactivation
of the enzyme telomerase reverses degenerative traits. Baker et al. now find that clearing
senescent cells delays age-related dysfunction
in the setting of BubR1 insufficiency. Surely,
researchers will now keenly explore these and
other routes for targeting cellular senescence,
in search of a viable strategy that would allow
us to get older more healthily.
Daniel S. Peeper is at the Netherlands Cancer
Institute, Division of Molecular Genetics,

1066 CX Amsterdam, the Netherlands.

e-mail: d.peeper@nki.nl
1. Kirkwood, T. B. L. & Austad, S. N. Nature 408,
233238 (2000).
2. Sharpless, N. E. & DePinho, R. A. Nature Rev. Mol.
Cell Biol. 8, 703713 (2007).
3. Baker, D. J. et al. Nature 479, 232236 (2011).
4. Collado, M. & Serrano, M. Nature Rev. Cancer 10,
5157 (2010).
5. Kuilman, T., Michaloglou, C., Mooi, W. J. & Peeper,
D. S. Genes Dev. 24, 24632479 (2010).
6. Kuilman, T. & Peeper, D. S. Nature Rev. Cancer 9,
8194 (2009).
7. Rodier, F. & Campisi, J. J. Cell Biol. 192, 547556
(2011).
8. Campisi, J. Cell 120, 513522 (2005).
9. Pajvani, U. B. et al. Nature Med. 11, 797803
(2005).
10. Baker, D. J. et al. Nature Cell Biol. 10, 825836
(2008).
11. Krizhanovsky, V. et al. Cell 134, 657667 (2008).
12. Jaskelioff, M. et al. Nature 469, 102106 (2011).

N A N OTEC H N OLOGY

A molecular
four-wheel drive
Nanoscale systems designed to imitate functions from the macroscopic world lead
to a new appreciation of the complexity needed to actuate motion at the limits of
miniaturization. A nanoscale car is the latest example. See Letter p.208
PA U L S . W E I S S

specially designed molecule that has

four motorized wheels is reported
by Kudernac etal.1 on page 208 of this
issue. By depositing the molecules on a surface
and providing them with sufficiently energetic
electrons from the tip of a scanning tunnelling microscope, the authors were able to drive
some of the molecules in a specific direction,
much like a car with four-wheel drive. Previous examples of actuated single-molecule
motion have been reported24, but none with
the complex action to continue moving in
the same direction across a surface like the
system devised, synthesized and operated by
Kudernac and co-authors.
Biological systems have inspired the design,
construction and operation of materials and
nanometre-scale devices that have analogous functions on all scales4. In top-down
approaches, nanoscale components have
been put together whose functions roughly
mimic aspects of those of the kidneys, muscles, nose and so on46. On the smallest scales,
molecules have been designed and synthesized
to demonstrate various capabilities, and, more
importantly, to explore the limits of miniaturization, operation and efficiency for both
natural and artificial machines. For example,
single-molecule electronic switches and simple

molecules that move in response to various

stimuli have been demonstrated24. Typically,
these synthetic systems are less flexible than
their biological inspirations. This makes it
easier to couple experimental results from
such systems to theory and simulations ranging from quantum chemistry to mechanical
engineering. From such studies, we ultimately
hope to learn some of natures secrets of robust
operation, high energy-conversion efficiency
and hierarchical function and action.
In such work, the forces that dominate
the macroscopic world around us, such as
gravity, are less important than the forces
that rule the nanoscale and biological worlds,
such as van der Waals and capillary forces.
Nevertheless, there are similarities between
our everyday world and the nanoscale world:
a car must have not only the ability to accelerate, but also brakes and traction; likewise,
nanoscale actuated motion depends on
balancing applied forces with those that hold
structures in place. Kudernac etal.1 solve this
problem, as others have, by balancing surface
interactions and thermal energy with forces
that can be applied through actuation, so that
their molecules move only on stimulation,
rather than by diffusion.
Scanning probe microscopes, especially
scanning tunnelling microscopes (STMs),
have been used to push, pull and place atoms,

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RESEARCH NEWS & VIEWS

STM tip

Atom

Figure 1 | Movement by microscope. Scanning tunnelling microscopes

(STMs) have been pivotal to studies of atomic-scale motion. a,b,At first,
STMs were used to follow the diffusion of atoms (a) and molecules (b) on
surfaces. Red arrows indicate movement of atoms or molecules; the atomic
structure of the end of the STM tip is shown. c,d,STMs were then used to

molecules and supramolecular assemblies on

surfaces79 (Fig.1). In complementary studies, mobile atoms and molecules on surfaces
have been tracked using STMs to measure
nanoscale interaction strengths between
molecules, and between molecules and surfaces1012. In studies of both diffusion and
manipulation, some of the molecules have
been designed to include parts that test modes
of motion. For example, do molecular wheels
roll or slide? At least in some cases, they roll12.
And can synthetic molecules be made to run
unidirectionally on tracks, like biomolecular
motors? Thus far, they can do so only with
carefully programmed tracks and fuel13.
Many of these molecules are analogous to
familiar objects, and the similarities are often
emphasized in schematic depictions of the
molecules that leave out chemical groups and/
or structural distortions caused by interactions
of the molecules with surfaces. But such groups
and distortions have significant consequences
for their structures and motion on surfaces
that often render our intuition about their
behaviour incorrect. For example, although
steps just one atom high on a surface can pose
significant barriers for atoms, molecules and
supramolecular structures moving on that
surface, the relatively large molecules used
in many studies distort so as to climb up or
down such steps with ease12. In some cases, the
presence of a moving molecule can even cause
the atoms of the steps to reorganize, to make
stronger contacts with molecules14.
With their inspired design of a four-wheeled
molecule, Kudernac etal.1 have gone a sizeable
step further than previous studies. The wheels
are actually molecular ratchets (rotary motors
that turn in a single direction), some or all of
which can be actuated to move when sufficiently energetic electrons are supplied by an
STM tip. The authors observed that, on surfaces, the nanoscale car lurches forward by a
fraction of a nanometre if each wheel rotates in
the same direction. When driven repeatedly in
this way, the molecules exhibited net forward

position atoms into precise structures (c) and to push molecules to study
nanometre-scale interactions (d). e,Kudernac etal.1 have now used an STM
as an energy source for molecular motion the STM provided electrons
(blue arrow) to drive car-like molecules with four motorized wheels (purple)
across a surface. Black arrows indicate the turning of the wheels.

motion, although the route taken was not

perfectly linear presumably owing to mismatches between atoms of the surface and those
of the wheels and so the distance travelled
was not quite as far as theoretically possible
(see Fig.2 of the paper1). The authors used the
STM not only to manipulate their molecules,
but also, in a less perturbative mode, to image
the progress of the molecules, an approach that
has been used in earlier studies79,11.
A complication of this work is that the
chemical synthesis used by Kudernac etal. to
make their molecules does not (yet) control the
attachment of the wheels to ensure that they
all turn in the same direction. In fact, only a
fraction of the molecules synthesized had all
four wheels optimally connected. Separating these cars from the others using chemical
methods prior to deposition on a surface might
be desirable, but this is prohibitively difficult
at present. However, the properly constructed
cars can be differentiated by function (that is,
by their directional movement in response
to stimulation) once they are deposited on a
surface and probed individually.
In addition, the operation of the molecules
depends on whether they land in the correct
orientation on the surface akin to having a
car factory in which half the fully assembled
vehicles are immobilized when they drop off
the production line, because they land on their
roofs or sides. The key difference is that, in
chemical syntheses, trillions of molecules are
synthesized in parallel. It has, however, been
possible to design asymmetrical molecules in
other systems that always orient themselves
in a particular way upon deposition15. The
orientational and other impediments in the
present work1 will, therefore, ultimately be
cleared away through molecular-level understanding of the systems and further design
constraints.
In developmental and evolutionary biology,
gains of function are key points in time.
The work of Kudernac etal. represents just
such a gain in function for nanotechnology:

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2011 Macmillan Publishers Limited. All rights reserved

molecules with multiple motors can now be

synthesized, deposited and operated to move
directionally across a surface. The authors
system provides a tremendous opportunity to
understand how molecular motors can interact, and how moleculesurface interactions
affect molecular motion. It also, however,
points out many of the complications that
will come with creating increasingly complex
syntheses and increasingly functional nanostructures. Nonetheless, we can expect further
significant gains of function as our understanding of, and intuition for, the nanoscale
world grows, and as accessible synthetic
structures become ever more complex and
sophisticated.
Paul S. Weiss is at the California
NanoSystems Institute, and in the
Departments of Chemistry & Biochemistry
and Materials Science & Engineering,
University of California, Los Angeles,
Los Angeles, California 90095, USA.
e-mail: psw@cnsi.ucla.edu
1. Kudernac, T. et al. Nature 479, 208211 (2011).
2. Donhauser, Z. J. et al. Science 292, 23032307
(2001).
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