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PNAS 107 (21): 9730-9735

Copyright © 2010 by the National Academy of Sciences.


Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity

Sivan Henis-Korenblit1, Peichuan Zhang, Malene Hansen2, Mark McCormick, Seung-Jae Lee3, Michael Cary, and Cynthia Kenyon4

Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158

Contributed by Cynthia Kenyon, March 11, 2010 (sent for review December 2, 2009)

Abstract: When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response is activated. This ER stress response restores ER homeostasis by coordinating processes that decrease translation, degrade misfolded proteins, and increase the levels of ER-resident chaperones. Ribonuclease inositol-requiring protein–1 (IRE-1), an endoribonuclease that mediates unconventional splicing, and its target, the XBP-1 transcription factor, are key mediators of the unfolded protein response. In this study, we show that in Caenorhabditis elegans insulin/IGF-1 pathway mutants, IRE-1 and XBP-1 promote lifespan extension and enhance resistance to ER stress. We show that these effects are not achieved simply by increasing the level of spliced xbp-1 mRNA and expression of XBP-1’s normal target genes. Instead, in insulin/IGF-1 pathway mutants, XBP-1 collaborates with DAF-16, a FOXO-transcription factor that is activated in these mutants, to enhance ER stress resistance and to activate new genes that promote longevity.

Key Words: aging • daf-2 • insulin signaling • unfolded protein response

Author contributions: S.H.-K. and C.K. designed research; S.H.-K., P.Z., M.H., M.M., and S.-J.L. performed research; S.H.-K., M.C., and C.K. analyzed data; and S.H.-K. and C.K. wrote the paper.

1Present address: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 52900, Israel.

2Present address: Sanford-Burnham Medical Research Institute, Program of Development and Aging, La Jolla, CA 92037.

3Present address: Division of Molecular and Life Sciences/I-BIO/World Class University Program IT Convergence Engineering, Pohang University of Science & Technology, Pohang, 790-784 South Korea.

The authors declare no conflicts of interest.

Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, (accession no. GSE20148).

This article contains supporting information online at

4To whom correspondence should be addressed. E-mail: cynthia.kenyon{at}

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