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Research Perspective|Volume 2, Issue 10|pp 742—747

EAK proteins: novel conserved regulators of C. elegans lifespan

Travis W. Williams1, Kathleen J. Dumas1,2, Patrick J. Hu1,3,4
  • 1Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
  • 2Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
  • 3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
  • 4Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
* These authors contributed equally
Received: September 14, 2010Accepted: October 23, 2010Published: October 25, 2010
https://doi.org/10.18632/aging.100214

Copyright: © 2010 Williams et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

FoxO transcription factors (TFs) extend lifespan in invertebrates and may participate in the control of human longevity. The role of FoxO TFs in lifespan regulation has been studied most extensively in C. elegans, where a conserved insulin/insulin-like growth factor signaling (IIS) pathway and the germline both control lifespan by regulating the subcellular localization of the FoxO transcription factor DAF-16. Although the control of FoxO activity through modulation of its subcellular localization is well established, nuclear translocation of FoxO is not sufficient for full FoxO activation, suggesting that undiscovered inputs regulate FoxO activity after its translocation to the nucleus. We have recently discovered a new conserved pathway, the EAK (enhancer-of-akt-1) pathway, which acts in parallel to the Akt/PKB family of serine-threonine kinases to regulate DAF-16/FoxO activity. Whereas mutation of Akt/PKB promotes the nuclear accumulation of DAF-16/FoxO, mutation of eak genes increases nuclear DAF-16/FoxO activity without influencing DAF-16/FoxO subcellular localization. Thus, EAK proteins regulate the activity of nuclear DAF-16/FoxO. Two EAK proteins, EAK-2/HSD-1 and EAK-7, influence C. elegans lifespan and are conserved in mammals. The discovery of the EAK pathway defines a new conserved FoxO regulatory input and may have implications relevant to aging and the pathogenesis of aging-associated diseases.