Serum Levels of α-Klotho Are Correlated with Cerebrospinal Fluid Levels and Predict Measures of Cognitive Function

Kundu, Payel; Zimmerman, Benjamin; Quinn, Joseph F.; Kaye, Jeffrey; Mattek, Nora; Westaway, Shawn K.; Raber, Jacob

doi:10.3233/jad-215719

Cited by 21 publications

(20 citation statements)

References 43 publications

(49 reference statements)

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“…It has been thought that Klotho levels in the blood and CSF are independent. Contrary to that view, some investigators have recently reported that serum and CSF levels correlate strongly, and high levels predict better cognitive function ( Kundu et al, 2022 ). This is of major interest for future clinical studies, especially concerning drugs or other treatments that increase Klotho.…”

Section: Klotho and Neurodegenerative Diseasesmentioning

confidence: 97%

“…In the 55–85 age group, however, levels were more consistently low. CSF levels are also quite variable ( Kundu et al, 2022 ). In view of this, results obtained from small groups should be interpreted with caution.…”

Section: Klotho and Neurodegenerative Diseasesmentioning

confidence: 99%

“…Cardiovascular: Chen K, et al, 2021 ; Freunlich et al, 2021 ; Manrique et al, 2016 ; Myung et al, 2022 ; Martin-Nunez et al, 2022 ; Olejnik et al, 2018 , 2020 ; Tyrenkov et al, 2021 ; Wang F and Zheng, 2022 ; Yang et al, 2015 . Brain: Dias et al, 2021 ; Driscoll et al, 2021 ; Cararo-Lopes et al, 2017 ; Fung et al, 2022 ; Hanson et al, 2021 ; Kundu et al, 2022 ; Laszczyk et al, 2017 ; Mytych, 2022 ; Nietzel et al, 2021; Sanz et al, 2021 . Cancer: Doi et al, 201 ; Ewendt et al, 2021 ; Rubinek and Wolf, 2016 ; Sachdeva et al, 2020 .…”

Section: Klotho and Neurodegenerative Diseasesunclassified

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Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Prud’homme

Kurt²,

Wang

2022

Front. Aging

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The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.

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Section: Klotho and Neurodegenerative Diseasesmentioning

confidence: 97%

Section: Klotho and Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Klotho and Neurodegenerative Diseasesunclassified

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Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Prud’homme

Kurt²,

Wang

2022

Front. Aging

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“…The serum and cerebrospinal fluid levels of α-KL are positively correlated with and predict scores on the Mini-Mental State Examination and Clinical Dementia Rating, regardless of sex (16). Additionally, a study related to the most common neurodegenerative disease (i.e., Alzheimer's disease) has shown that the disease leads to decreased α-KL expression in the brain, and the overexpression of α-KL improves cognitive function by inhibiting neuroinflammation, promoting amyloid β-protein (Aβ) clearance, and mitigating Tau pathology (17).…”

Section: Introductionmentioning

confidence: 94%

Effects of chronic kidney disease on cognitive function and α-klotho expression in hippocampus

Huang¹,

Li²,

Tan³

et al. 2022

Transl Androl Urol

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Background: Alpha-klotho (α-KL) is not only related to the regulation of calcium-phosphorus metabolism, and fibrosis in chronic kidney disease (CKD), it is also involved in the regulation of many cognitive disorders.We conducted this study to investigate the effects of CKD on cognitive dysfunction and α-KL.Methods: Doxorubicin was used to induce a CKD model, which was validated by weight, 24-hour urine protein quantification, serum creatinine (Cr), blood urea nitrogen (BUN), and kidney hematoxylin-eosin (HE) staining. The Morris water maze (MWM) paradigm was used to assess the effects of CKD on cognitive behavior. The expression of α-KL in the hippocampus was detected using real-time quantitative polymerase chain reaction, Western blot, and immunohistochemistry (IHC).Results: (I) In the CKD group, the weight of the rats increased slowly (P<0.001), 24-hour urine protein increased (P<0.05), and Cr (P=0.026) and BUN levels (P=0.003) increased; (II) HE staining showed that in the CKD group there were changes in the structure, fibrosis, and inflammatory infiltration of the renal tissues, and changes in the structure, cell necrosis, and neuronal degeneration of the hippocampus; (III) in the MWM experiment, the escape latency of the CKD group was prolonged compared to that of the control group (P=0.043, 0.023), and the number of crossing the platform was reduced (P=0.003); (IV) in the CKD group, the expressions of α-KL messenger ribonucleic acid (P=0.0005) and α-KL protein (P=0.0005) in the hippocampus were downregulated. The IHC results showed that the expression of α-KL protein in the hippocampal region III cornus ammonis (CA3) of the CKD group region was also downregulated, and the α-KL-positive cells (P=0.019) and mean optical density (P=0.015) were decreased. Conclusions:The expression of α-KL appears to effect the cognitive function of CKD rats; thus, it may be a valuable target in the treatment of CKD with cognitive impairment.

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“…High α-klotho levels were shown to especially benefit apoE4 carriers [ 8 , 16 ]. However, in people between 39 and 90 years of age, serum and CSF levels of α-klotho are positively correlated and predict scores on both the Mini-Mental State Examination test and the Clinical Dementia Rating regardless of sex or APOE genotype [ 168 ]. There is a robust positive relationship between α-klotho and apoE levels in the amygdala in irradiated non-human primates [ 18 ].…”

Section: Contributions Of the Periphery To Cns Insulin Actionsmentioning

confidence: 99%

Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites

2022

Self Cite

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The concept of insulin resistance has been around since a few decades after the discovery of insulin itself. To allude to the classic Charles Dicken’s novel published 62 years before the discovery of insulin, in some ways, this is the best of times, as the concept of insulin resistance has expanded to include the brain, with the realization that insulin has a life beyond the regulation of glucose. In other ways, it is the worst of times as insulin resistance is implicated in devastating diseases, including diabetes mellitus, obesity, and Alzheimer’s disease (AD) that affect the brain. Peripheral insulin resistance affects nearly a quarter of the United States population in adults over age 20. More recently, it has been implicated in AD, with the degree of brain insulin resistance correlating with cognitive decline. This has led to the investigation of brain or central nervous system (CNS) insulin resistance and the question of the relation between CNS and peripheral insulin resistance. While both may involve dysregulated insulin signaling, the two conditions are not identical and not always interlinked. In this review, we compare and contrast the similarities and differences between peripheral and CNS insulin resistance. We also discuss how an apolipoprotein involved in insulin signaling and related to AD, apolipoprotein E (apoE), has distinct pools in the periphery and CNS and can indirectly affect each system. As these systems are both separated but also linked via the blood–brain barrier (BBB), we discuss the role of the BBB in mediating some of the connections between insulin resistance in the brain and in the peripheral tissues.

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Serum Levels of α-Klotho Are Correlated with Cerebrospinal Fluid Levels and Predict Measures of Cognitive Function

Cited by 21 publications

References 43 publications

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Effects of chronic kidney disease on cognitive function and α-klotho expression in hippocampus

Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites

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