The Vascular Secret of Klotho

The klotho enzyme can be manipulated to slow aging in laboratory animals, and more circulating klotho is associated with enhanced cognitive function. Like many of the mechanisms found to modestly slow aging in short-lived species in the laboratory, the activities of klotho touch on many systems in the body and are far from completely cataloged. This is an example of some of the more speculative areas of investigation:

Klotho-deficient mice manifest a phenotype resembling accelerated human ageing. Klotho-deficient mice have a short lifespan, and overexpression of Klotho in mice extends lifespan significantly in comparison with normal mice, which is taken as proof of the concept that Klotho is associated with longevity. In a human population study, Klotho gene variations were found to be associated with life extension. Of particular interest was the finding that Klotho deficiency in mice was associated with a severe vascular phenotype of arteriosclerosis, impaired endothelial function, and impaired angiogenesis.

Klotho protein in mammals is present in different isoforms, as a membrane-bound protein and as a soluble form. Membrane Klotho confers tissue target specificity for FGF23. The function of Klotho as an obligatory coreceptor for FGF23 explains the nearly identical phenotypes that are observed in knockout mice lacking either Klotho or FGF23. Soluble Klotho is secreted into serum, urine, and cerebrospinal fluid. Serum Klotho or Klotho fragments can have humoral actions on tissues far distant from the site of biosynthesis. This is based on the observation of generalized involvement of tissues and organs outside the Klotho expression tissues in the prematurely ageing phenotype of Klotho-deficient mice and on the finding that administration of soluble Klotho ameliorated the premature ageing-related features, such as growth retardation, organ atrophy, and vascular calcification.

Experimental studies have shown that soluble Klotho, when delivered as a humoral factor, can protect the vasculature. Klotho gene delivery by adenoviral vector increased endothelium-dependent nitric oxide synthesis and prevented adverse vascular remodeling in an arteriosclerotic, obese rat model. Results from several in vitro models point toward a direct effect of soluble Klotho on vascular tissue. Recently, soluble Klotho has been shown to regulate vascular tonus, and a nitric oxide stimulatory ability was confirmed in vitro.

Uremia is potentially a state of Klotho deficiency based on decreased concentrations both at the tissue level and in the circulation, although determinations of serum Klotho levels are problematic. It is of high priority to better understand whether deficiency of Klotho contributes to the reduced longevity and other many severe complications in patients with chronic kidney disease, which are accompanied by a dramatic increase in the rate of cardiovascular morbidity and death.

In different experimental models soluble Klotho has been shown to protect against acute kidney injury, renal fibrosis, uremic cardiomyopathy, vascular calcification, and endothelial dysfunction. These observations are very important not only to understand the pathogenetic mechanisms involved, but also with respect to the development of future and more effective treatments and prophylactic measures, including replacement/substitution of the potentially missing hormone. In this context it is essential to know whether the uremic state is associated with reduced circulating levels of Klotho, whether local vascular production is reduced, and whether vascular tissue is an additional source of humoral Klotho. It is still an open question whether Klotho is present in the vasculature under physiological conditions, and, if so, whether it is changed in the uremic state.



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