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Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice

Colin Selman^*, Steven Lingard^*, Agharul I. Choudhury^*, Rachel L. Batterham^*, Marc Claret^*, Melanie Clements^*, Faruk Ramadani, Klaus Okkenhaug, Eugene Schuster, Eric Blanc, Matthew D. Piper, Hind Al-Qassab^*, John R. Speakman^||, Danielle Carmignac^¶, Iain C. A. Robinson^¶, Janet M. Thornton, David Gems, Linda Partridge and Dominic J. Withers^*,1

^* Centre for Diabetes and Endocrinology, Department of Medicine, Rayne Institute, and

Centre for Research on Ageing, Department of Biology, University College London, London, UK;

Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge, UK;

European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK;

^|| Aberdeen Centre for Energy Regulation and Obesity (ACERO), School of Biological Sciences, University of Aberdeen, Aberdeen, UK; and

^¶ Division of Molecular Neuroendocrinology, Medical Research Council National Institute of Medical Research, London, UK

¹Correspondence: Centre for Diabetes and Endocrinology, Rayne Institute, University College London, University St., London, UK. E-mail: d.withers{at}ucl.ac.uk

Recent evidence suggests that alterations in insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) can increase mammalian life span. For example, in several mouse mutants, impairment of the growth hormone (GH)/IGF1 axis increases life span and also insulin sensitivity. However, the intracellular signaling route to altered mammalian aging remains unclear. We therefore measured the life span of mice lacking either insulin receptor substrate (IRS) 1 or 2, the major intracellular effectors of the IIS receptors. Our provisional results indicate that female Irs1^–/– mice are long-lived. Furthermore, they displayed resistance to a range of age-sensitive markers of aging including skin, bone, immune, and motor dysfunction. These improvements in health were seen despite mild, lifelong insulin resistance. Thus, enhanced insulin sensitivity is not a prerequisite for IIS mutant longevity. Irs1^–/– female mice also displayed normal anterior pituitary function, distinguishing them from long-lived somatotrophic axis mutants. In contrast, Irs2^–/– mice were short-lived, whereas Irs1^+/– and Irs2^+/– mice of both sexes showed normal life spans. Our results therefore suggest that IRS1 signaling is an evolutionarily conserved pathway regulating mammalian life span and may be a point of intervention for therapies with the potential to delay age-related processes.—Selman, C., Lingard, S., Choudhury, A. I., Batterham, A. L., Claret, M., Clements, M., Ramadani, F., Okkenhaug, K., Schuster, E., Blanc, E., Piper, M. D., Al-Qassab, H., Speakman, J. R., Carmignac, D., Robinson, I. C. A., Thornton, J. M., Gems, D., Partridge, L., Withers, D. J. Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice.

Key Words: aging • longevity • insulin signaling