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Research Paper|Volume 2, Issue 9|pp 567—581

Klotho interferes with a novel FGF-signalling pathway and insulin/Igf-like signalling to improve longevity and stress resistance in Caenorhabditis elegans

Marie-Thérèse Château1, Caroline Araiz3, Simon Descamps2, Simon Galas1
  • 1University of Montpellier1, Faculty of Pharmacy and Pharmaceutical Sciences, B.P. 14491, F-34093 Montpellier Cedex 5, France
  • 2University of Montpellier2, Faculty of Sciences, F34095 Montpellier Cedex 5, France
  • 3CNRS, CRBM-UMR 5237, F-34293 Montpellier Cedex 5, France
  • 4Present address: Institute of Healthy Ageing, Room 324, The Darwin Building University College London, London WC1E 6BT, UK
Received: August 21, 2010Accepted: September 7, 2010Published: September 9, 2010
https://doi.org/10.18632/aging.100195

Copyright: © 2010 Château 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

Klotho exerts anti-aging properties in mammals in two different ways. While membrane-bound Klotho, which is primarily expressed in the kidney, acts as an obligate co-receptor of FGF23 to regulate phosphate homeostasis, secreted Klotho, resulting from the shedding of the KL1-KL2 ectodomain into the bloodstream, inhibits Insulin/IGF1 signalling. However, the underlying molecular mechanisms are not fully understood. Here, we investigated the biological role of Klotho inCaenorhabditis elegans.

Two redundant homologues of the klotho gene exist in C. elegans and encode predicted proteins homologous to the β glucosidase-like KL1 domain of mammalian Klotho. We have used a genetic approach to investigate the functional activity of Klotho in C. elegans. Here, we report that whereas Klotho requires EGL-15 (FGFR) and EGL-17 to promote longevity and oxidative stress resistance, it is not involved in the regulation of fluid homeostasis, controlled by LET-756. Besides revealing a new post-developmental role for EGL-17, our data suggest that the KL1 form of Klotho is involved in FGF23-independent FGF signalling. We also report a genetic interaction between Klotho and the DAF-2 (Ins/IGF1R)/DAF-16 (FOXO) pathway. While the regulation of longevity requires functional DAF-2/DAF-16 signalling, the control of oxidative stress resistance involves a DAF-2- independent, DAF-16-dependent pathway, suggesting that Klotho may target either DAF-2 or DAF-16, depending of environmental conditions. Thus, the predictive KL1 form of Klotho appears to crosstalk with both FGF and Insulin/IGF1/FOXO pathways to exert anti-aging properties in C. elegans.