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

Château MT, Araiz C, Descamps S, Galas S - Aging (Albany NY) (2010)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: University of Montpellier1, Faculty of Pharmacy and Pharmaceutical Sciences, F-34093 Montpellier Cedex 5, France.

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 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.

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Klotho requires a functional EGL-17/EGL-15 signalling pathway to improve oxidative stress resistance by a daf-16-dependent but daf-2-independent genetic pathway.Adult worms of the indicated genotype were pre-induced to either klotho or control RNAi at 20°C, then subjected to oxidative treatment by 25mM Menadione during 72 h and their viability scored. Controls were performed in the absence of Menadione. Results are mean values +/- SD of at least four independent experiments. Statistical analysis was done by a Student t-test at *p < 0.05 signification level. At least 100 worms were scored for each test condition. All experiments were performed at 20°C.
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Figure 5: Klotho requires a functional EGL-17/EGL-15 signalling pathway to improve oxidative stress resistance by a daf-16-dependent but daf-2-independent genetic pathway.Adult worms of the indicated genotype were pre-induced to either klotho or control RNAi at 20°C, then subjected to oxidative treatment by 25mM Menadione during 72 h and their viability scored. Controls were performed in the absence of Menadione. Results are mean values +/- SD of at least four independent experiments. Statistical analysis was done by a Student t-test at *p < 0.05 signification level. At least 100 worms were scored for each test condition. All experiments were performed at 20°C.

Mentions: As shown in Figure 5, both the egl-15 (n484) reduction-of-function allele and the daf-16 (mgDf50) deletion mutant, fed with either control or klotho RNAi, displayed an increased sensitivity to oxidative stress in similar fashion to the N2 (wild-type) worms fed with klotho RNAi only. As expected, similar results were obtained when the egl-17(n1377) reduction-of-function allele was used in place of the egl-15(n484) mutant (not shown).


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

Château MT, Araiz C, Descamps S, Galas S - Aging (Albany NY) (2010)

Klotho requires a functional EGL-17/EGL-15 signalling pathway to improve oxidative stress resistance by a daf-16-dependent but daf-2-independent genetic pathway.Adult worms of the indicated genotype were pre-induced to either klotho or control RNAi at 20°C, then subjected to oxidative treatment by 25mM Menadione during 72 h and their viability scored. Controls were performed in the absence of Menadione. Results are mean values +/- SD of at least four independent experiments. Statistical analysis was done by a Student t-test at *p < 0.05 signification level. At least 100 worms were scored for each test condition. All experiments were performed at 20°C.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2984606&req=5

Figure 5: Klotho requires a functional EGL-17/EGL-15 signalling pathway to improve oxidative stress resistance by a daf-16-dependent but daf-2-independent genetic pathway.Adult worms of the indicated genotype were pre-induced to either klotho or control RNAi at 20°C, then subjected to oxidative treatment by 25mM Menadione during 72 h and their viability scored. Controls were performed in the absence of Menadione. Results are mean values +/- SD of at least four independent experiments. Statistical analysis was done by a Student t-test at *p < 0.05 signification level. At least 100 worms were scored for each test condition. All experiments were performed at 20°C.
Mentions: As shown in Figure 5, both the egl-15 (n484) reduction-of-function allele and the daf-16 (mgDf50) deletion mutant, fed with either control or klotho RNAi, displayed an increased sensitivity to oxidative stress in similar fashion to the N2 (wild-type) worms fed with klotho RNAi only. As expected, similar results were obtained when the egl-17(n1377) reduction-of-function allele was used in place of the egl-15(n484) mutant (not shown).

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: University of Montpellier1, Faculty of Pharmacy and Pharmaceutical Sciences, F-34093 Montpellier Cedex 5, France.

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 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.

Show MeSH
Related in: MedlinePlus