New effect of Insulin on Lifespan of Worm C. elegans

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A new independent way insulin influences the livespan of the worm

C. elegans over the protein SKN-1 was discovered by researchers

of Albert-Ludwig-University Freiburg, Germany and Harvard Medical

School and published in Cell, (Volume 132, Issue 6 from March 21,

2008).

They found that increasing the activity of SKN-1 extends lifespan.

From: http://www.pr.uni-freiburg.de/pm/2008/pm.2008-03-25.108/

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 age-related 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 is

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 age-related 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.

Citation:

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

M.A. Tullet,1,5 Maren Hertweck,2,5 Jae Hyung An,1,3,5 ph

Baker,1 Ji Yun Hwang,3 Shu Liu,2 Riva P. Oliveira,1 Ralf

Baumeister,2,4 and T. Blackwell1

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.