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Science 327 (5970): 1223-1228

Copyright © 2010 by the American Association for the Advancement of Science

Sestrin as a Feedback Inhibitor of TOR That Prevents Age-Related Pathologies

Jun Hee Lee,1 Andrei V. Budanov,1 Eek Joong Park,1 Ryan Birse,2 Teddy E. Kim,3 Guy A. Perkins,4 Karen Ocorr,2 Mark H. Ellisman,4 Rolf Bodmer,2 Ethan Bier,3,* Michael Karin1,*

Abstract: Sestrins are conserved proteins that accumulate in cells exposed to stress, potentiate adenosine monophosphate–activated protein kinase (AMPK), and inhibit activation of target of rapamycin (TOR). We show that the abundance of Drosophila sestrin (dSesn) is increased upon chronic TOR activation through accumulation of reactive oxygen species that cause activation of c-Jun amino-terminal kinase and transcription factor Forkhead box O (FoxO). Loss of dSesn resulted in age-associated pathologies including triglyceride accumulation, mitochondrial dysfunction, muscle degeneration, and cardiac malfunction, which were prevented by pharmacological activation of AMPK or inhibition of TOR. Hence, dSesn appears to be a negative feedback regulator of TOR that integrates metabolic and stress inputs and prevents pathologies caused by chronic TOR activation that may result from diminished autophagic clearance of damaged mitochondria, protein aggregates, or lipids.

1 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093–0723, USA.
2 Development and Aging Program, Neuroscience, Aging and Stem Cell Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
3 Section of Cell and Developmental Biology, UCSD, La Jolla, CA 92093–0349, USA.
4 National Center for Microscopy and Imaging Research and Department of Neurosciences, UCSD, La Jolla, CA 92093–0608, USA.

* To whom correspondence should be addressed. E-mail: ebier{at} (E.B.); karinoffice{at} (M.K.)

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