CeKlotho opens a new road for investigation in worm aging

goddess of Greek mythology who spins the thread of life. Mice deficient for KL exhibit many changes that occur during aging, including arteriosclerosis, osteoporosis, infertility, and cognitive decline and have a short life span [1]. The Klotho gene encodes several isoforms in mammals, which include a membrane-bound and two secreted forms. The circulating isoforms result from the proteolytic cleavage of the transmembrane KL ectodomain (and/or from alternative splicing) and contain KL1 and KL2 sequences, or only KL1, which are homologous to beta-glucosidase. KL proteins are multifunctional [2]. KL deglycosylates the steroid beta-glucuronides and the calcium chanel transient receptor potential vanilloid 5, TRPV5. It also acts as a cofactor essential for the recognition of fibroblast growth factor FGF 23 which plays a key role in the control of phosphate homeostasis and vitamin D metabolism. The multiple physiological effects of KL also include inhibition of the intracellular insulin/IGF1 receptor (IIRc) signalling cascade. Indeed, mice overexpressing KL live 30% longer than wild-type mice and show a significant resistance to oxidative stress associated with moderate resistance to insulin/IGF-1, which may partly explain why these mice live longer than wild-type [3]. However the respective role of different KL isoforms in aging and the molecular mechanisms altered in transgenic mice that are functionally relevant for lifespan regulation are still poorly understood. In this issue, Château et al. [4] report the first identification and characterization of Klotho genes homologues in Caenorhabditis elegans. Two CeKlotho genes are present in the C. elegans genome which both encode predicted proteins with similarity to the beta-Commentary on glucosidase-like KL1 domain of mammalian KL. RNAi inactivation of CeKlotho reduced wild-type worm's lifespan but did not affect the lifespan of mutants for the IIRc pathway, including mutant for the receptor DAF-2, the PI3K/AGE-1 and the FOXO transcription factor DAF-16. Yamamoto et al. previously published that treatment of mammalian cells with the secreted Klotho protein inhibits IIRc signalling, activates FOXO, induces SOD2 expression and reduces oxidative damages and apoptosis induced by paraquat [5]. In agreement with those data CeKlotho RNAi treated animals were also more sensitive to oxidative stress than control worms. Overall those data support the idea that the regulation of IIRc pathway by KL is conserved between C. elegans and mammals and that this pathway constitutes a relevant target for lifespan control by KL in mice. Interestingly, CeKlotho RNAi did not affect the lifespan of catalytic mutants for IIRc DAF-2 while it …