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.
Highlights
In 1997 Kuro-o et al [1] reported a mutant mouse displaying a phenotype similar to that of premature aging in humans
The phenotype of shortened lifespan, multiple organ degeneration, vascular calcification (VC), cardio-vascular disease (CVD) and frailty were attributed to the abolished expression of the klotho gene, named after the Greek goddess of fate, κλωθω′, who spun the thread of life [1]
Klotho has subsequently been characterized as one of a family of related proteins. These are all single-pass transmembrane proteins that include α, β, and - Klotho isoforms [3,4,5], the latter two discovered based on their homology with α-klotho [6, 7]. β -Klotho is mainly expressed in the liver, but is found in the kidney, gut and spleen. It regulates the activity of members of the fibroblast growth factor (FGF) family, including FGF-21 and FGF-19. -Klotho is expressed in the skin and the kidney and has yet to be ascribed defined functions [3, 7]. α-Klotho comprises five exons and structurally its cognate protein is composed of a large extracellular domain followed by a transmembrane domain and a small domain of 11 residues comprising the intracellular C-terminus [8, 9]
Summary
In 1997 Kuro-o et al [1] reported a mutant mouse displaying a phenotype similar to that of premature aging in humans. The phenotypic characteristics of genetic Klotho deficiency, such as bone disease, VC, CVD increased FGF23 levels, hyperphosphatemia, and premature mortality, resembles the uremic accelerated aging phenotype in man [58, 83] In keeping with these observations, Klotho deficiency in CKD has been reported to enhance renal tubule and vascular cell senescence leading to defective endothelial function and impaired vasculogenesis [84]. Current literature supports such a thesis, and has indicated that the development and progression of CKD is significantly associated with a dysregulated FGF23Klotho pathway, resulting in hyperphosphatemia and endothelial dysfunction [8, 18, 53,54,55].
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