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Science 326 (5949): 140-144

Copyright © 2009 by the American Association for the Advancement of Science

Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span

Colin Selman,1,* Jennifer M. A. Tullet,2 Daniela Wieser,3 Elaine Irvine,1 Steven J. Lingard,1 Agharul I. Choudhury,1 Marc Claret,1 Hind Al-Qassab,1 Danielle Carmignac,4 Faruk Ramadani,5 Angela Woods,6 Iain C. A. Robinson,4 Eugene Schuster,3 Rachel L. Batterham,1 Sara C. Kozma,7 George Thomas,7 David Carling,6 Klaus Okkenhaug,5 Janet M. Thornton,3 Linda Partridge,2 David Gems,2 Dominic J. Withers1,8,{dagger}

Abstract: Caloric restriction (CR) protects against aging and disease, but the mechanisms by which this affects mammalian life span are unclear. We show in mice that deletion of ribosomal S6 protein kinase 1 (S6K1), a component of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway, led to increased life span and resistance to age-related pathologies, such as bone, immune, and motor dysfunction and loss of insulin sensitivity. Deletion of S6K1 induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)–activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. Our results demonstrate that S6K1 influences healthy mammalian life-span and suggest that therapeutic manipulation of S6K1 and AMPK might mimic CR and could provide broad protection against diseases of aging.

1 Institute of Healthy Ageing, Centre for Diabetes and Endocrinology, Department of Medicine, University College London, London WC1E 6JJ, UK.
2 Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK.
3 European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
4 Division of Molecular Neuroendocrinology, Medical Research Council National Institute for Medical Research, London NW7 1AA, UK.
5 Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge CB22 3AT, UK.
6 Cellular Stress Group, Medical Research Council Clinical Sciences Centre, Imperial College, London W12 0NN, UK.
7 Department of Cancer and Cell Biology, Genome Research Institute, University of Cincinnati, Cincinnati, OH 45237, USA.
8 Metabolic Signaling Group, Medical Research Council Clinical Sciences Centre, Imperial College, London W12 0NN, UK.

* Present address: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen AB24 2TZ, UK.

{dagger} To whom correspondence should be addressed. E-mail: d.withers{at}ucl.ac.uk or d.withers{at}imperial.ac.uk.

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