DR MARC VERMULST
Ageing answers
Dr Marc Vermulst is working to unravel the secrets behind the ageing process. He hopes
that a deeper understanding of the relationship between RNA transcription errors and
ageing might lead to novel approaches for treating and preventing age-related illnesses
Could you offer an insight into your
background and how you became involved
in ageing research? Why are you so
passionate about this field?
I am primarily interested in basic biological
questions that can teach us about life itself.
This desire led to my interest in ageing
research; I wanted to understand why humans
grow older. I realised that every individual alive
today is destined to age and die. We share this
fate with every person that was alive in the past
and those to be born in the future. I think that
understanding this fate is valuable on its own,
as well as from a medical perspective. Most
diseases that are currently endemic in Western
society are age-related. These diseases, which
include cancer, heart disease and Alzheimer’s,
place an enormous financial burden on medical
infrastructure, patients and their families.
Since ageing is the primary risk factor for all of
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these conditions, it is reasonable to conclude
that if we understood the ageing process more
fully, we would be able to ameliorate or even
prevent some of these diseases. Understanding
ageing is therefore one of the most important
tasks facing modern medicine today.
How did you come to focus your
investigations on biological errors in RNA?
For a long time, researchers have suspected
that biological errors, particularly DNA
mutations, contribute to human ageing. I
studied DNA mutations for many years, but
the more I learned, the more I started to
suspect that we were overlooking an important
middleman. To send instructions to the cell for
protein synthesis, DNA first makes a copy of
itself called RNA. Like DNA, RNA contains all
the information that is required to successfully
build a protein, but it is much more compact
DR MARC VERMULST
and easily transferrable, so that it can be shared
with the rest of the cell. Since RNA is not
protected by the same defence mechanisms as
DNA, however, errors occur more frequently.
To what extent might your work impact
understanding and management of
age-related diseases, such as Alzheimer’s
and Parkinson’s?
Our current results are extremely promising. I
hope that our work can uncover a completely
new mechanism that contributes to ageing
and age-related diseases. What’s especially
exciting is that the mechanism we propose is
not unique to any disease in particular. Instead,
it seems to be connected to the very heart of
ageing itself. So, if we can fix it, we may be
able to delay numerous age-related conditions
at once, while simultaneously decreasing the
rate at which they progress. An important
breakthrough in this context is our finding that
dietary restriction can reverse the shortened
lifespan caused by RNA errors. An enormous
amount of work by many other researchers has
previously shown that dietary restriction can
also extend the lifespan of worms, flies, mice
and rats and delay the onset of age-related
diseases in monkeys. As a result, it is highly
recommended to limit your daily intake of
calories if you want to stave off age-related
diseases. Our results now suggest a new
molecular rationale for lifestyle.
Partnership and knowledge exchange are
important to your work; with whom do
you collaborate?
My most important collaborators are Dr Jeffrey
Strathern, the Deputy Director of the National
Cancer Institute in Frederick, Maryland,
and Dr Dorothy Erie, my former advisor at
the University of North Carolina in Chapel
Hill. I’m also inspired by the work of Dr Paul
Doetsch, a researcher at Emory University, who
demonstrated that RNA errors do not only
occur in test tubes, but in living cells as well.
Research conducted by both Doetsch and Dr
Larry Loeb from the University of Washington,
shaped my thinking when I decided to pursue
this project. My research also benefits from
the contributions of team members Suraiya
Haroon and Agnes Holczbauer.
What is next for your research and how do
you intend to reach these goals?
I have set two important goals for the future:
to find the reason why transcription errors
increase with age, and demonstrate in mice
and human cell lines how these errors affect
ageing cells. With these experiments I may
be able to revolutionise understanding of
ageing and age-related diseases and open up
a completely new discipline within mutation
research. The only way to accomplish these
goals is to work hard and be passionate.
It’s in the RNA
In a laboratory within The Children’s Hospital of Philadelphia,
a group of researchers is investigating the biological basis for
ageing and disease, with a particular emphasis on the role of RNA
AROUND THE WORLD, people are living
longer. As average life expectancies stretch,
medical infrastructures and budgets struggle
to keep up with the rising demands put
upon them by age-related illnesses such
as Alzheimer’s and Parkinson’s. In order to
effectively tackle such disorders, researchers
are increasingly looking to understand more
about the biological underpinnings of ageing.
One researcher hoping to further understanding
of this field is Dr Marc Vermulst, an assistant
professor within the Center for Mitochondrial
and Epigenomic Medicine at The Children’s
Hospital of Philadelphia. He is currently two
years into a five-year National Institutes of
Health (NIH)-funded project entitled ‘Nongenetic mutations in aging organisms’.
AGEING ERRORS
For a long time, like many scientists
investigating the biological basis of ageing,
Vermulst’s focus was on DNA – the so-called
‘blueprint of life’. It is DNA that instructs cells
how to build the proteins that are necessary
to perform all manner of vital tasks within the
body, from dispersing oxygen to delivering
energy. Errors within the DNA can wreak
havoc with protein construction. For this
reason, DNA is highly protected, meaning that
mutations are relatively rare.
Transcription errors caused by faulty RNA,
however, are far more frequent. RNA is
essentially a temporary copy of DNA that is
used to carry instructions for protein synthesis
to different locations within a cell. RNA is less
protected than DNA, and as such mutations
are much more frequent. However, when
Vermulst began studying this area, the extent
to which such errors impacted cellular health
was poorly understood and it was for this
reason that he decided to turn his attention
to this field.
YES TO YEAST
To understand more about RNA, Vermulst’s
group monitored two yeast cell lines that
had been genetically modified to display
error-prone transcription. Yeast is interesting
to study as it ages similarly to complex
organisms. This, combined with the fact that it
is easy to manipulate on the genetic level and
can be grown in enormous quantities, makes
it extremely valuable from a researcher’s
perspective. “Model organisms such as yeast
can be used as living test tubes to understand
human ageing and disease,” Vermulst confirms.
One promising area for the
treatment and prevention of
age-related diseases is associated
with another of the researchers’
findings: that proteotoxicity caused
by transcription errors actively
decreases cell lifespan
Vermulst’s initial investigations produced a
number of significant findings. Firstly, the
researchers discovered that transcription errors
can induce proteotoxic stress, whereby the
misfolding of a protein impairs the cell function,
thus sensitising the cell to the expression of
genes associated with protein-folding illnesses,
such as Huntington’s disease. Secondly, it was
found that transcription errors were capable
of overextending the protein quality control
machinery within cells, thereby causing the
persistence of toxic proteins by allowing them
to escape degradation and grow in terms of
toxicity and aggregation rate. “This may increase
the severity of these diseases, and affect the age
at which they present themselves,” Vermulst
clarifies. A third interesting discovery was
that transcription errors increase with age,
meaning that older cells are more vulnerable to
proteotoxic stress than younger ones. Overall,
Vermulst’s findings represent a molecular
explanation as to why ageing is associated with
the onset of age-related disease and, as such, a
novel avenue for the treatment of such illnesses.
PUTTING CELLS ON A DIET
One promising area for the treatment and
prevention of age-related diseases is associated
with another of the researchers’ findings:
proteotoxicity caused by transcription errors
actively decreases cell lifespan. This can
have a negative impact on a person’s health,
particularly if the affected cells are difficult to
replace, such as neurons.
Vermulst therefore set out to explore whether
this effect was permanent or reversible.
Since existing research had already indicated
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NON-GENETIC MUTATIONS
IN AGING ORGANISMS
OBJECTIVE
To understand how certain biological errors
contribute to ageing. These errors, which
occur during protein expression, could play a
role in various diseases, including Alzheimer’s
and Parkinson’s. Errors will be monitored
with highly sensitive techniques, the lifespan
of cells with increased error rates will be
recorded and the molecular underpinnings of
the findings will be documented.
KEY COLLABORATORS
Dorothy Erie, Professor, Department of
Chemistry, University of North Carolina in
Chapel Hill • Jeffrey Strathern, Deputy
Director, National Cancer Institute, Frederick,
Maryland • Mara Duncan, Professor,
Department of Developmental and Cellular
Biology, University of Michigan in Ann Arbor
PARTNERS
Agnes Holczbauer, Research Associate;
Suraiya Haroon, Postdoctoral Researcher,
The Children’s Hospital of Philadelphia,
Pennsylvania
FUNDING
National Institute on Aging – grant no.
5R00AG041809
CONTACT
Dr Marc Vermulst
Department of Pathology and Laboratory
Medicine
The Children’s Hospital of Philadelphia
The Colket Translational Research Building
6th Floor – Room 6014
Philadelphia, Pennsylvania 19104, USA
T +1 267 425 2117
E [email protected]
DR MARC VERMULST received his MSc
in Biology from the University of Utrecht,
The Netherlands, and his PhD in Pathology
from the University of Washington, USA.
His postdoctoral training was carried out
at the California Institute of Technology,
USA, and the University of North Carolina
at Chapel Hill, USA. His research focuses on
the molecular underpinnings of the ageing
process itself and the role that biological
errors play in this process. These studies
aim to reveal how ageing results in agerelated diseases and the basic biology that
constrains our lifespan.
that dietary restriction can delay the onset
of age-related pathology and extend cell
lifespans, the group decided to test whether
such an approach could reverse the impact
of transcription errors. What they found was
that dietary restriction did indeed reverse
these negative effects, via the manipulation of
protein quality control pathways, and as such
allowed the cells to function better and live
longer. This finding paves the way for further
research and, potentially, the development of
novel preventive and curative strategies.
From left to right: Agnes Holczbauer, Dr Vermulst and
Suraiya Haroon in the lab.
MOVING ON TO BIGGER THINGS
Having made their initial discoveries in
yeast, Vermulst and his co-workers are now
turning their attention to the cell lines of
higher organisms, including worms, mice and
humans. “We are modifying the enzyme that
synthesises RNA molecules, so that a higher
number of errors occur when RNA molecules
are made,” Vermulst clarifies. “It is not easy,
and I suspect that our biggest obstacle will be
generating these organisms – although we are
already extremely close.” The aim is to increase
transcription errors within these cells in order
to test their hypothesis that this will accelerate
ageing both at the cellular and organismal
level, increasing susceptibility to age-related
diseases. This will represent a breakthrough
in understanding the molecular aetiology of
such illnesses.
Vermulst’s studies are supported by a
complete arsenal of modern biological
technologies, including electron microscopy,
mass spectrometry and liquid chromatography
with mass spectrometry analysis. “My
favourite tools are microscopy experiments
with fluorescent proteins and dyes, and the
latest techniques for RNA analysis and DNA
editing,” Vermulst reveals. “It is very exciting
being a biologist in today’s world, because
more is possible than ever before.”
OLDER AND WISER
Vermulst and his colleagues have no plans
to stop their investigations once they have
successfully demonstrated that transcription
errors accelerate ageing both at the cellular and
organismal level. Instead, they shall continue to
improve understanding in this emerging area by
turning their attention to establishing exactly
how and why transcription error rates increase
as cells age and, concomitantly, how these can
be minimised or even avoided.
Until now, the researchers have not reached a
definitive answer. Vermulst does, however, have
a theory: “Personally, I suspect that oxidative
damage is the main reason why RNA errors
increase with age,” he suggests. “If this is true,
our findings will tie in to almost every aspect of
human ageing, because they would provide a
connection between two of the most important
aspects of human ageing: oxidative stress and
protein dysfunction.” Since oxidative stress is
associated with numerous diseases, including
several age-related neurodegenerative disorders,
any findings in this area could have far-reaching
and significant applications. “It is indeed an
exciting prospect,” Vermulst confirms.
Ageing predisposes humans to disease
Alzheimer disease
Death rate/ 100.000
INTELLIGENCE
Cardiovasular disease
1,500
400
1,500
300
1,000
200
1,000
500
100
500
0
0
0 24 34 44 54 64 74 84 5 +
- - 8
15 25 35 45 55 65 75
0
0 24 34 44 54 64 74 84 5 +
- - 8
15 25 35 45 55 65 75
Age
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Cancer
2,000
0
15
4
4
4
4
4 4
4 +
- 2 5 - 3 5 - 4 5 - 5 5 - 6 5 - 7 5 - 8 85
6
7
2
5
4
3