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.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481361 | PMC |
http://dx.doi.org/10.3389/fendo.2020.00560 | DOI Listing |
Alzheimers Dement
December 2024
The Jackson Laboratory, Bar Harbor, ME, USA.
Background: Determining the precise genetic mechanisms that contribute to LOAD, both in coding and noncoding variants, will enable a deeper understanding of pathogenesis and advance preclinical models for the testing of targeted therapeutics.
Methods: We have introduced candidate genetic variants in the EPHA1, BIN1, CD2AP, SCIMP, KLOTHO, PTK2B, ADAMTS4, IL1RAP, IL34, and PTPRB loci into a sensitized mouse model already harboring humanized amyloid-beta, APOE4, and Trem2.R47H alleles knocked in to a C57BL/6J background.
Alzheimers Dement
December 2024
The Jackson Laboratory, Bar Harbor, ME, USA.
Background: Apolipoprotein E4 (APOE4), a common variant of APOE, is a major genetic risk factor for Alzheimer's disease (AD), but APOE4 carriers do not always develop AD. Several large-scale genetic studies have identified a common haplotype of the aging factor klotho that modify disease risk in APOE4 carriers. In humans, klothoharbors two common missense variants (rs9536314, p.
View Article and Find Full Text PDFSci Rep
January 2025
Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
α-Klotho (KLA) is a type-1 membranous protein that can associate with fibroblast growth factor receptor (FGFR) to form co-receptor for FGF23. The ectodomain of unassociated KLA is shed as soluble KLA (sKLA) to exert FGFR/FGF23-independent pleiotropic functions. The previously determined X-ray crystal structure of the extracellular region of sKLA in complex with FGF23 and FGFR1c suggests that sKLA functions solely as an on-demand coreceptor for FGF23.
View Article and Find Full Text PDFJ Nephrol
December 2024
Nephrology and Dialysis Unit, Genomics of Renal Diseases and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy.
Sci Rep
December 2024
Division of Nephrology, Affiliated Hospital of Hebei University, Baoding, China.
Klotho has been importantly linked to atherosclerosis, but little is known about its specific role. This study investigates the mechanism by which Klotho enhances the stability of atherosclerotic plaques in chronic kidney disease. apoE-/- knockout mice and C57BL/6 mice underwent 5/6 nephrectomy and then klotho-NC and klotho-mimic groups were set up to be fed a high-fat chow diet and a dummy group was created to be fed a normal chow diet.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!