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Klotho, Aging, and the Failing Kidney.

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 ?-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.

SUBMITTER: Buchanan S

PROVIDER: S-EPMC7481361 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Klotho, Aging, and the Failing Kidney.

Buchanan Sarah S Combet Emilie E Stenvinkel Peter P Shiels Paul G PG

Frontiers in endocrinology 20200827

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 ...[more]

PMID: 32982966

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Project description:Introduction:Sirtuin1 (SIRT1) acts as an anti-aging protein due to anti-apoptotic, anti-oxidative and anti-inflammatory effect and is implicated in several diseases including diabetes or cardiovascular problems. SIRT1 renal overexpression indicates oxidative stress. Similarly, ?Klotho was primarily exposed as anti-aging factor. It is primary produced in kidney. It's deficiency is associated with progression of chronic kidney disease and heart disorders. Purpose:The aim of the study was to assess the serum concentration of sirtuin1 and ?Klotho in hemodialysis (HD) patients compared to healthy volunteers in regard to age, blood pressure control, residual kidney function (RKF), diabetes, cardiovascular disease, dialysis vintage and type of dialyzer. Patients and Methods:The serum level of SIRT1 and ?Klotho was evaluated using ELISA tests in 103 HD patients, median age 67 years and in 21 volunteers. Blood pressure, RRF, echocardiography and dialysis parameters were assessed. HD group was divided according to the presence/absence of RKF. Results:The serum SIRT1 level was higher (28.4 vs 2.71ng/mL, p<0.0001) and ?Klotho was lower (433.9 vs 756.6pg/mL, p<0.0001) in HD then in control group. ?Klotho was lower in those without RKF (387.2 vs 486.2pg/mL, p=0.028). SIRT1 positively correlated with hemodialysis vintage. ?Klotho negatively correlated with left ventricular posterior wall thickness. There was no significant relationship between SIRT1 and ?Klotho level and age, blood pressure control, type of dialyzer, Kt/V and diabetes. Multivariate analysis revealed association of SIRT1 with ejection fraction (B -0.72; p=0.32). Conclusion:Elevated SIRT1 and lower ?Klotho concentration are associated with impaired kidney function. The decrease in levels of ?Klotho may also indicate heart hypertrophy in hemodialysis patients. The role of anti-aging proteins, particularly SIRT1 as biomarkers/predictors of oxidative stress, inflammation and cardiovascular diseases need further examination.

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Klotho, Aging, and the Failing Kidney.

Publications

Klotho, Aging, and the Failing Kidney.

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