Klotho interferes with a novel FGF-signalling pathway and insulin/Igf-like signalling to improve longevity and stress resistance in Caenorhabditis elegans.
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 in Caenorhabditis elegans. Two redundant homologues of the klotho gene exist in C. elegans and encode predicted proteins homologous to the  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.
Château
Marie-Thérèse
MT
University of Montpellier1, Faculty of Pharmacy and Pharmaceutical Sciences, F-34093 Montpellier Cedex 5, France.
Araiz
Caroline
C
Descamps
Simon
S
Galas
Simon
S
D000375:Aging / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000502:physiology*; D005966:Glucuronidase / Q000235:genetics / Q000502:physiology*; D007328:Insulin / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D000090265:Klotho Proteins; D008136:Longevity / Q000502:physiology; D023421:Models, Animal; D008969:Molecular Sequence Data; D011972:Receptor, Insulin / Q000502:physiology; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology; D014882:Water-Electrolyte Balance / Q000502:physiology
D029742:Caenorhabditis elegans Proteins; C112493:EGL-15 protein, C elegans; C105157:Egl-17 protein, C elegans; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D007334:Insulin-Like Growth Factor I; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin; D005966:Glucuronidase; D000090265:Klotho Proteins