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Researchers at Freiburg University help to discover new effect of insulin

Newly discovered role in ageing

Freiburg, Mar 20, 2008

Researchers at Freiburg University help to discover new effect of insulin

The tiny, 1 mm long nematode C. elegans is one of the most important model organisms for research on insulin signaling and ageing.

Researchers of the Albert-Ludwigs-Universität Freiburg,
in a research collaboration with their colleagues of Harvard Medical School in Boston, USA,
discover a novel function of insulin that affects ageing and longevity.

The study that will be published in the March 21 issue of the science magazine Cell describes
how insulin, through the activity of an enzyme recently described by the Freiburg research
team, blocks one of the most important cellular stress regulators, a protein called SKN-1.
Increasing the activity of SKN-1 extends lifespan. SKN-1 controls a genetic network called the
phase-2-detoxification pathway that helps to protect cells and tissues against damage through
oxidative stress. Oxidative stress is the consequence of increased levels of the so called free
radicals, generated as byproducts of the cellular metabolism and also through environmental
toxins. This latest discovery was the result of experiments performed in the intestinal tract of
the nematode C. elegans, a model organism frequently used to study aspects of human agerelated
disorders.

Only recently, the Freiburg research team led by Ralf Baumeister had shown that an enzyme
called SGK-1 in the insulin signaling pathway helps to control lifespan. „At the same time our
colleagues at the Joslin Diabetes Center of Harvard Medical School discovered another gene
affecting longevity, encoding the stress regulator SKN-1“, explains Prof. Baumeister, an author
of the recent Cell publication. „The most obvious thing to do was to compare our data and
collaborate. We discovered that we had approached the same phenomenon from two sides“.

Taking into account the many roles of insulin in the organism this novel function of insulin may
require close attention. The publication suggests that insulin, under certain circumstances,
might reduce the cellular defense against oxidative stress more than previously anticipated.

One of the expectations now is that, through activating SKN-1, the organismal resistance
against chronic diseases and longevity can be increased. The research could be equally
important for a better understanding of diabetes and many of its complications, some of the
most prominent are atherosclerosis and renal defects.
„But the most significant impact of our findings will be that on ageing research“, both research
teams agree. „Although we already know since 1993 of the importance of insulin singaling for
the control of organismal ageing, most of its details are still enigmatic“, explains Baumeister.
Until now, the researchers focused on a single genetic swich, the transcription factor FOXO, as
the most important factor controlling lifespan. FOXO is switched off under normal conditions
by insulin, and is equally important for the diabetes metabolism, stem cell maintenance, and
tumor suppression. FOXO also regulates genes of the oxidative stress response. Reduced
insulin signaling in C. elegans, for example through manipulating SGK-1, also activates a
FOXO factor called DAF-16 that helps to protect against stress and expands lifespan.

This novel study now revealed the existence of SKN-1 as a second genetic switch that is also
inhibited by insulin, but independent of FOXO. The data also suggest that SKN-1 controls a
distinct genetic program of stress defence and anti-aging. „We felt like archaeologists
discovering a secret treasure chamber. Activating SKN-1 was all that was needed to increase
longevity of the worm, and this will open an entirely new research field“, says Baumeister, who
iass Director of the Freiburg Center for Systems Biology ZBSA aims at understanding the
details of this complex regulatory network of ageing.

It will be important now to repeat the experiments in higher organisms. In mammals, insulin
and the related insulin-like growth factor are both involved in an intricate network that is not
yet understood in detail. However, as both teams agree, novel findings discovered in C. elegans
could frequently be reproduced in mice and humans.

The Freiburg research team uses C. elegans as an animal model for a number of human agerelated
diseases. Their work in the past repeatedly helped to a better understanding of
Alzheimer’s and Parkinson’s Disease, and also contributed to research in muscular dystrophies.
The study conducted at the University of Freiburg was financially supported by the German
Ministery of Research (BMBF), a Landesstiftung grant of the State Baden-Württemberg, the
Fonds der Chemischen Industrie Germany, the German Research Council, and the European
Community.


About ZBSA – The Freiburg Center of Systems Biology

ZBSA is an interdisciplinary research center funded by the State Baden-Württemberg and the
Albert-Ludwigs-Universität Freiburg. This interdisciplinary center is supported by all science
faculties of the university. In its brand-new facilities, experimental scientists from Biology and
Medicine and theoretical scientists from Physics and Mathematics collaborate with robotics and
computer specialists for a better understanding of the complex interplay of genes and proteins
in the organism and during diseases. ZBSA is the central facility for the scientific projects that
are funded by the German Excellence Initiative as the result of a national competition.

Please contact for further information:
Prof. Dr. Ralf Baumeister
ZBSA Zentrum für Biosystemanalye
ZBMZ (Faculty of Medicine), Bioinformatics & Molecular Genetics (Faculty of Biology)
Schänzlestr. 1
D-79104 Freiburg i.Brsg.
Tel. +49-761-203 8350
Fax. +49-761-203 8351
mobil: +49-1520-986 3097
www.celegans.de
Email: baumeister@celegans.de

Citation:
Cell, Volume 132, Issue 6 vom 21. März 2008

Jennifer M.A. Tullet,1,5 Maren Hertweck,2,5 Jae Hyung An,1,3,5 Joseph Baker,1 Ji Yun Hwang,3 Shu Liu,2 Riva P. Oliveira,1 Ralf
Baumeister,2,4 and T. Keith Blackwell,1
1 Section on Developmental and Stem Cell Biology, Joslin Diabetes Center; Department of Pathology, Harvard Medical School; Harvard
Stem Cell Institute, 1 Joslin Place, Boston, MA, 02215, USA
2 Center of Biochemistry and Molecular Cell Research (ZBMZ, Faculty of Medicine), Bioinformatics and Molecular Genetics (Faculty of
Biology), University of Freiburg, Schänzlestr. 1, D-79104 Freiburg, Germany
3 Protein Network Research Center, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul, 120-749, Republic of Korea
4 Center for Systems Biology (ZBSA), University of Freiburg, D-79104 Freiburg, Germany
5 These authors contributed equally to this work.

SUMMARY
Insulin/IGF-1-like signaling (IIS) is central to growth and metabolism and has a conserved role in
aging. In C. elegans, reductions in IIS increase stress resistance and longevity, effects that require the
IIS inhibited FOXO protein DAF-16. The C. elegans transcription factor SKN-1 also defends against
oxidative stress by mobilizing the conserved phase 2 detoxification response. Here we show that IIS
not only opposes DAF-16 but also directly inhibits SKN-1 in parallel. The IIS kinases AKT-1, -2, and
SGK-1 phosphorylate SKN-1, and reduced IIS leads to constitutive SKN-1 nuclear accumulation in
the intestine and SKN-1 target gene activation. SKN-1 contributes to the increased stress tolerance and
longevity resulting from reduced IIS and delays aging when expressed transgenically. Furthermore,
SKN-1 that is constitutively active increases life span independently of DAF-16. Our findings indicate
that the transcription network regulated by SKN-1 promotes longevity and is an important direct target
of IIS.