KL

The KL gene encodes two proteins: one membrane protein and one secreted transcript that acts as a circulating hormone. KL regulates INS, Wnt, and FGF23 signalling. Mice mutant for KL show multiple signs of accelerated ageing. The accelerated ageing phenotype of KL deficient mice is similar to that observed in FGF23 deficient mice. KL binds FGF receptors and is a co-factor essential for the activation of the receptor. In this process KL acts as a scaffold protein and tethers the FGF receptor to FGF23 by its C-terminal tail, conferring stability to the complex. In contrast, overexpression of KL in mice increases lifespan by 20-30% (perhaps through repression of intracellular INS/IGF1 signals), dramatically improves renal function, and protects against neurodegenerative diseases such as Alzheimer’s and Parkinson’s. KL enhances neuroprotection and normal cognition, in part, by optimising synaptic functions. Peripheral expression of a KL fragment enhanced brain function in young and ageing mice, in addition to an alpha-synuclein transgenic mouse model of Parkinson’s disease. The KL fragment induced cleavage of an NMDAR subunit and increased synaptic plasticity. Injection of KL into the central nervous system resulted in enhanced learning and memory 6 months after injection. KL alleles have also been implicated in human longevity and age-related diseases. Even though its other functions remain a mystery, KL may also be involved in calcium metabolism and in a vitamin D endocrine system. Premature ageing phenotypes in mice mutant for KL are largely rescued by keeping the animals on a vitamin-D-deficient diet. It is plausible that KL plays some role in human ageing but more work is necessary to confirm this notion and elucidate the mechanisms involved.