Klotho, Aging, and the Failing Kidney

Sarah Buchanan, Emilie Combet, Peter Stenvinkel, Paul G Shiels, Sarah Buchanan, Emilie Combet, Peter Stenvinkel, Paul G Shiels

Abstract

Klotho has been recognized as a gene involved in the aging process in mammals for over 30 years, where it regulates phosphate homeostasis and the activity of members of the fibroblast growth factor (FGF) family. The α-Klotho protein is the receptor for Fibroblast Growth Factor-23 (FGF23), regulating phosphate homeostasis and vitamin D metabolism. Phosphate toxicity is a hallmark of mammalian aging and correlates with diminution of Klotho levels with increasing age. As such, modulation of Klotho activity is an attractive target for therapeutic intervention in the diseasome of aging; in particular for chronic kidney disease (CKD), where Klotho has been implicated directly in the pathophysiology. A range of senotherapeutic strategies have been developed to directly or indirectly influence Klotho expression, with varying degrees of success. These include administration of exogenous Klotho, synthetic and natural Klotho agonists and indirect approaches, via modulation of the foodome and the gut microbiota. All these approaches have significant potential to mitigate loss of physiological function and resilience accompanying old age and to improve outcomes within the diseasome of aging.

Keywords: kidney; Klotho; aging; phosphate; senotherapeutic.

Copyright © 2020 Buchanan, Combet, Stenvinkel and Shiels.

Figures

Figure 1
Figure 1
Schematic representation of the role of Klotho in the regulation of bone and mineral metabolism.
Figure 2
Figure 2
Schematic representation of a range of possible and existing Klotho based senotherapies.

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