Endocrine Abstracts (2007) 14 S25.1

Hormones help you live longer - the threat of Klotho

M Kuro-o

The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

A defect in klotho gene expression in mice leads to a syndrome resembling aging, including a shortened life span, hypogonadism, growth arrest, hypoactivity, skin atrophy, muscle atrophy, hearing loss, premature thymic involution, cognition impairment, motor neuron degeneration, arteriosclerosis, osteopenia, soft tissue calcification, and pulmonary emphysema among others. In contrast, overexpression of the klotho gene extends life span in the mouse. Thus, the klotho gene functions as an aging suppressor gene. The klotho gene encodes a single-pass transmembrane protein and is expressed in limited tissues, notably in the kidney and brain. The extracellular domain of Klotho is shed and secreted in the blood, raising the possibility that Klotho protein itself may function as a humoral factor.

Extended life span in transgenic mice that overexpress Klotho is associated with increased resistance to insulin/IGF1 and oxidative stress, mechanisms for the suppression of aging evolutionarily conserved from worms to mammals. Klotho may affect aging processes partly through its ability to inhibit insulin/IGF1 signaling and to reduce oxidative stress.

Mice defective in fibroblast growth factor-23 (FGF23) exhibit aging-like phenotypes similar to those observed in Klotho-deficient mice, suggesting that Klotho and FGF23 may function in a common signal transduction pathway(s). My laboratory has shown that Klotho binds to multiple FGF receptors (FGFRs) and enhances the ability of FGF23 to activate FGF signaling. FGF23 was originally identified as a hormone that inhibited phosphate reabsorption in the kidney. In fact, both Klotho-deficient mice and FGF23-deficient mice exhibit elevated serum phosphate levels. In addition, many aging-like phenotypes in these mice are rescued by restriction of dietary phosphate or ablation of vitamin D activity. These findings imply a novel concept that FGF signaling and phosphate metabolism may participate in the regulation of aging in mammals.

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