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PROFESSOR THOMAS BOSCH
110INTERNATIONAL INNOVATION
Forever young
Humanity has always been fascinated by the quest for eternal life.
Now, new findings in the genome of simple freshwater animals could
bring us one step closer by uncovering a real-life longevity gene
WHILE THE EXISTENCE of a magical ‘elixir
of life’ which grants the drinker immortality
has long been accepted as myth, the hunt
for the potion’s gift is still a reality for many
scientists, at least in essence. The search for
the source of eternal life has led Professor
Thomas Bosch from the University of Kiel’s
Zoological Institute to examine a biologically
immortal organism in the hope that it may
reveal clues about the ageing process.
HYDRA
Scientists have long been fascinated by a
group of simple metazoans called Hydra,
ever since 18th Century Swiss naturalist,
Abraham Trembley used their extensive
regenerative capacities to demonstrate
that living creatures can form de novo. This
went against the prevailing theory of the
time, which was that everything in Nature
emerged ‘preformed’.
A genus of small, simple, freshwater
cnidarians; Hydra are close relatives of
jellyfish and can be found in ponds, lakes
and streams worldwide. Hydra reproduce
by asexual budding and, incredibly, many
researchers have concluded that they are
immune to the effects of old age – although
a scientific consensus has yet to be reached.
This finding was first reported in an important
1998 study that appeared in Experimental
Gerontology, and since then much emphasis
has been placed on examining the genetic
factors that might lead to this seemingly
never-ending ability to reproduce and avoid
ageing, or ‘senescence’.
But what makes these Hydra different
from humans and other animals that do
experience senescence? Researchers believe
that two factors play an important role in
their apparent immortality – the ability of
their stem cells to function continuously, and
the consistent maintenance of an immune
system, processes which decline rapidly in
ageing humans.
FOXO GENES
On 4 August 1997, Jeanne Calment died at the
age of 122 years and 164 days – the oldest human
lifespan ever recorded. Whilst this maximum
span is well established, the environmental and
genetic factors that lead to such incredible feats
remain largely a mystery. That said, research
has unearthed two genetic variants that are
associated with human longevity, the ε4 allele of
the apolipoprotein E gene (APOE) and markers in
the forkhead box O3A gene (FOXO3A).
Recent studies have indicated the FOXO3A
gene shows modest beneficial effects in survival
of nonagenarians and centenarians, which
has led to some scientists declaring it as the
only confirmed longevity-enabling gene in
humans. However, as Bosch explains, much is
still unknown about this intriguing gene: “It still
remains to be seen through which mechanisms
the as yet unidentified, underlying functional
variation in this gene contributes to the
longevity phenotype in humans”.
It is this uncertainty that led Bosch and his
team to examine the role of the closely related
FoxO gene in Hydra. The constantly selfrenewing nature of their stem cells was recently
demonstrated in all three of the stem cell
lineages that these animals possess, these being
ectodermal and endodermal, epitheliomuscular
and interstitial cells. This was achieved by the
ingenious in vivo tracking of individual enhanced
green fluorescent protein (eGFP) expressing
cells. With this knowledge, Bosch and his team
hoped they could investigate both the molecular
and genetic factors that lead to this state of
apparent eternal youth. In a breakthrough study
that appeared in Proceedings of the National
Academy of Science (PNAS) in 2012, they
showed that FoxO was a critical regulator of this
stem cell maintenance in Hydra.
EXCITING FINDINGS
To achieve this, the group analysed the
transcriptome signature for the three cell
INTELLIGENCE
UNDERSTANDING THE MOLECULAR
LOGIC OF STEM CELL BEHAVIOUR IN
THE SIMPLE METAZOAN HYDRA
OBJECTIVES
To understand the genetic basis of
biological immortality in Hydra, and
subsequently apply any findings to
improving understanding of the ageing
process in humans.
Recent studies have indicated how the FOXO3A gene shows
modest beneficial effects in survival of nonagenarians and
centenarians, which has led to some scientists declaring it as the
only confirmed longevity-enabling gene in humans
KEY COLLABORATORS
Professor Dr med Stefan Schreiber,
Professor Dr med Philip Rosenstiel,
Professor Dr rer nat Almut Nebel, Institute
of Clinical Molecular Biology, ChristianAlbrechts-University, Kiel
FUNDING
lineages, and found that among the cell-intrinsic
factors expressed in all of them, FoxO was very
prominent. With this knowledge, they conducted
transgene-mediated
gain-of-function
and
hairpin-mediated loss-of-function analyses of
the FoxO transcription factor in the hope that
they could consolidate their ideas. As expected,
the team found that the FoxO gene was strongly
expressed in all three cell lineages. In accordance
with their original hypothesis, they also found
that overexpression of FoxO stimulated stem
cell and progenitor cell proliferation, as well as
activating stem cell genes. Conversely, silencing
of the FoxO gene led to a down-regulation of
those very same stem cell genes. Importantly,
this silencing of the age-related gene resulted in
a down-regulation of the genes that control the
functionality of the innate immune system.
Based on these findings, Bosch proposed a new
model of the role of FoxO in Hydra immortality.
He proposed that these tiny cnidarians contain
high levels of FoxO in all of their stem cell
lineages, which plays a crucial role not only in
their capacity for continuous self-renewal, but
also their continuous maintenance of an innate
immune system. With this knowledge, Bosch’s
next challenge came in trying to translate this
animal model to humans.
APPLICATIONS IN HUMANS
Bosch’s research seems most pertinent when
one considers the intriguing similarities that
HYDRA IN AQUARIUM
exist between these simple animals and other,
more complex organisms, when it comes to the
role that genes play in ageing. Other studies
have shown that mutations in Daf16/FoxO in
Caenorhabditis elegans, a nematode worm,
reduces longevity, whereas overexpression
increases it. On top of this, these findings
also revealed FoxO as a molecular factor that
contributed to the early evolution of stem cells.
When taken together with the discovery that
similar mutations in the human FOXO3A have
also shown an association with increases in life
span, it seems plausible that findings in these
animals actually could be applied to people.
Furthermore, an important aspect of the study
– the maintenance of the innate immunity – is
of particular importance when looking at this
model in humans. It has been well documented
that the ageing process in humans results in
impairment of both the innate and adaptive
immunity (immunosenescence), as well as in
pro-inflammatory status (inflammaging).
With this in mind, Bosch believes these
findings may lead to a greater understanding
of the molecular and genetic mechanisms
behind ageing in humans, but realises that the
enormity of this task cannot be underestimated.
“Attempts to extend the lessons learned from
Hydra to more complex organisms, including
humans, will be challenging,” he explains.
“However, the recent study is a proof-ofprinciple that further investigation into Hydra
stem cells holds much promise.”
While his future experiments will carry on in
this vein, Bosch is also keen to examine the
importance of upstream events, which he
believes will be affected by environmental
factors. It is these factors that Bosch hopes
to turn his attention to next: “My lab is
currently very much focused on understanding
how environmental signals coming from
diet, microbiota, exercise and stress affect
signalling pathways upstream of FoxO and
the phosphorylation status of FoxO, using the
unique Hydra model system”.
Deutsche Forschungsgemeinschaft (DFG)
Clusters of Excellence programmes: The
Future Ocean and Inflammation at Interfaces
CONTACT
Professor Thomas Bosch
Professor of General Zoology
Christian-Albrechts-Universität zu Kiel
Mathematisch-Naturwissenschaftliche
Fakultät Zoologisches Institut
Am Botanischen Garten 1-9
24118 Kiel
Germany
T +49 431 880 4169
E [email protected]
www.bosch.zoologie.uni-kiel.de/
PROFESSOR THOMAS BOSCH studied
Biology at the University of Munich,
Germany and Swansea University, UK. He
earned his doctorate from the University
of Munich in 1986, before holding a
postdoctoral position at the University of
California, Irvine, USA. After working as
a Research Associate at the University of
Munich, he was appointed as Professor of
Zoology at the Friedrich Schiller University
of Jena in 1997. Since 2000, Bosch has
worked as Professor of General Zoology at
Kiel University. From 2010-13 he served as
Vice-President of Kiel University and was
responsible for Kiel University’s institutional
strategy and international relations. Bosch
is managing editor of Zoology, a member of
several national and international Academic
Committees and Boards, and is PI in the
International Max Planck Research School for
Evolutionary Biology. His awards include a
Dr honoris causa degree from St. Petersburg
State University, Russia.
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