• Open Access

dFOXO-independent effects of reduced insulin-like signaling in Drosophila

Authors

  • Cathy Slack,

    1. Institute of Healthy Ageing and GEE, University College London, Gower Street, London WC1E 6BT, UK
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  • Maria E. Giannakou,

    1. Institute of Healthy Ageing and GEE, University College London, Gower Street, London WC1E 6BT, UK
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    • Present addresses: M. Giannakou, Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK. M. Goss, Biochemical Pharmacology, William Harvey Research Institute, Charterhouse Square, London, EC1M 6BQ, UK.

  • Andrea Foley,

    1. Institute of Healthy Ageing and GEE, University College London, Gower Street, London WC1E 6BT, UK
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  • Martin Goss,

    1. Institute of Healthy Ageing and GEE, University College London, Gower Street, London WC1E 6BT, UK
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    • Present addresses: M. Giannakou, Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK. M. Goss, Biochemical Pharmacology, William Harvey Research Institute, Charterhouse Square, London, EC1M 6BQ, UK.

  • Linda Partridge

    1. Institute of Healthy Ageing and GEE, University College London, Gower Street, London WC1E 6BT, UK
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Linda Partridge, Institute of Healthy Ageing and GEE, University College London, Gower Street, London WC1E 6BT, UK. Tel.: +44 20 7679 2983; fax: +44 20 7679 7096; e-mail: l.partridge@ucl.ac.uk

Summary

The insulin/insulin-like growth factor-like signaling (IIS) pathway in metazoans has evolutionarily conserved roles in growth control, metabolic homeostasis, stress responses, reproduction, and lifespan. Genetic manipulations that reduce IIS in the nematode worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the mouse have been shown not only to produce substantial increases in lifespan but also to ameliorate several age-related diseases. In C. elegans, the multitude of phenotypes produced by the reduction in IIS are all suppressed in the absence of the worm FOXO transcription factor, DAF-16, suggesting that they are all under common regulation. It is not yet clear in other animal models whether the activity of FOXOs mediate all of the physiological effects of reduced IIS, especially increased lifespan. We have addressed this issue by examining the effects of reduced IIS in the absence of dFOXO in Drosophila, using a newly generated null allele of dfoxo. We found that the removal of dFOXO almost completely blocks IIS-dependent lifespan extension. However, unlike in C. elegans, removal of dFOXO does not suppress the body size, fecundity, or oxidative stress resistance phenotypes of IIS-compromised flies. In contrast, IIS-dependent xenobiotic resistance is fully dependent on dFOXO activity. Our results therefore suggest that there is evolutionary divergence in the downstream mechanisms that mediate the effects of IIS. They also imply that in Drosophila, additional factors act alongside dFOXO to produce IIS-dependent responses in body size, fecundity, and oxidative stress resistance and that these phenotypes are not causal in IIS-mediated extension of lifespan.

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