Physiological function of ageing suppression gene klotho and its role in development of adult disease

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Arteriosclerosis caused by aging is recognized to be a crucial risk factor of cardiovascular disease. We recently established Klotho mouse which causes age-related disorders including arteriosclerosis. However, no information on endothelial function of Klotho mouse or the pathophysiological role of klotho gene product as a circulating factor is available. We demonstrate that the vasodilator response of aorta and arterioles to acetylcholine was significantly attenuated in homozygous klotho mice as compared with wild-type mice. Parabiosis between wild-type and heterozygous klotho mice resulted in restoration of endothelial function in heterozygous Klotho mice. Nitric oxide metabolites (NO2- and NO3-) in urine are significantly lower in heterozygous Klotho mice (142 *16nmol/day) than wild-type mice (241* 28nmol/day). We also showed that kiotho mRNA expression is significantly decreased in spontaneously hypertensive rats, deoxycorticosterone acetate (DOCA) salt hypertensive rats and Otsuka Long-Evans Tokushima Fatty (OLETF) rats developing hypertension, obesity, insulin resistance, and hypertriglyceridemia.We conclude that the Klotho protein protects against the cardiovascular dysfunction through endothelium-derived NO production by humoral pathways.