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Submitted: January 30, 2024 | Approved: February 27, 2024 | Published: February 29, 2024

How to cite this article: Saiz-Figuerez MI, Nava E, Galindo MF, Jordan J. Is there a Place for Klotho in Alzheimer’s disease? J Sports Med Ther. 2024; 9: 001-010.

DOI: 10.29328/journal.jsmt.1001074

Copyright License: © 2024 Saiz-Figuerez MI, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Keywords: Alzheimer´s disease; Klotho; Neurodegenerative aging; Aβ clearance; FGF23; TGF-β; NF-kB; IGF-1; Wnt; Anti-aging

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Is there a Place for Klotho in Alzheimer’s disease?

Maria Isabel Saiz-Figuerez1, Nava E2, Galindo MF3 and Joaquin Jordan1*

1Área de Farmacología, Departamento de Ciencias Médicas, Facultad de Medicina de Albacete, Universidad de Castilla-La Mancha, Albacete, España
2Área de Fisiología, Departamento de Ciencias Médicas, Facultad de Medicina de Albacete, Universidad de Castilla-La Mancha, Albacete, España
3Área de Tecnología Farmacéutica, Departamento de Ciencias Médicas, Facultad de Farmacia, Universidad de Castilla-La Mancha, Albacete, España

*Address for Correspondence: Joaquin Jordan, Área de Farmacología, Departamento de Ciencias Médicas, Facultad de Medicina de Albacete, Universidad de Castilla-La Mancha, Albacete, España, Email:

Alzheimer’s disease, a major healthcare concern, lacks an effective pharmacological therapy to change its irreversible progression. In this work, we present Klotho, a protein associated with aging that is involved in the regulation of numerous physiological processes and is a serious candidate to be a pharmacological target to act on. Klotho’s mRNA has been found in neurons of a variety of brain regions (cortex, hippocampus). The best studied and prominent function of Klotho is as the co-receptor of fibroblast growth factor 23 (FGF23), through which Klotho controls renal phosphate excretion and vitamin D metabolism. Reduced serum levels of Klotho in mice have been associated with a shorter life expectancy and with numerous pathological conditions such as renal disease, vascular calcification, neurodegeneration, and others. Moreover, overexpression of Klotho leads to opposite effects resulting in increased survival rates. In this review we address different signaling pathways in which Klotho is involved in one way or another, focusing on those pathways that could serve as pharmacological targets to modify the evolution of Alzheimer’s disease. We describe how Klotho inhibits signaling cascades involved in cellular senescence, fibrosis, inflammation, and apoptosis all of which are mediated by tumor growth factor β (TGF- β), nuclear factor kappa K (NF- κ B), insulin-like growth factor 1 (IGF-1) or Wnt. We also highlight how Klotho is able to activate anti-inflammatory and antioxidant signaling pathways. Although there are no drugs that act specifically on Klotho, compounds currently on the market such as hormone-based drugs, pravastatin, losartan, fosinopril, and rapamycin have been shown to increase the expression of this protein and are also discussed.

When Aloise Alzheimer first described, back in the early 20th century, the anatomopathological abnormalities of Auguste Deter’s brain, he was unaware that he was opening the doors to the field of clinical research on dementias: a family of diseases, in addition to Alzheimer’s Disease (AD) itself, that includes others such as vascular dementia, Lewy body dementia, and frontotemporal dementia. The total number of new cases of dementia worldwide is increasing year by year. For example, between 1990 and 2019, AD prevalence rose from 2.9 million to 7.2 million, an increase of 147.7%, and is expected to affect more than 150 million people by 2050 [1].

Unfortunately, we currently have no effective pharmacological therapy capable of reversing the undesirable and irreversible evolution of AD. Possibly, the main cause of this failure is that, in many cases, AD is diagnosed in late stages, when the potential for improvement is very small. AD can be broadly classified into two major classes: familial and sporadic AD. The familial form is associated with mutations in three genes: Amyloid Precursor Protein (APP), presenilin 1, and presenilin 2. On the other hand, the sporadic late-onset form has been related to environmental factors such as the presence of heavy metals (e.g. lead, manganese, and cadmium), and other metals like aluminum and smoking. In addition to this, there are numerous genetic factors such as the Apolipoprotein E (APOE) gene and its gene variants Epigenetic mechanisms are also involved. Nevertheless, it is clear that the most important factor associated with sporadic AD is aging.

Aging, like all multifactorial physiological processes, is genetically regulated [2] and is characterized by disorders, often irreversible, of different tissues and organs [3] causing physiological dysfunctions that can lead to a state of disease. Different transcription factors and proteins have been associated with the programming machinery of aging such as p53, telomerase, and Klotho.

Klotho is a beta-glucosidase implicated in the control of autacoid-mediated functions. The history of klotho is linked to a paper published in 1997 where Makoto Kuro-o described a transgenic mouse with age-related disorders caused by a transgene insertion mutation. Homozygous mice showed phenotypes similar to those of patients with premature aging syndromes: arteriosclerosis, osteoporosis, age-related skin changes, and ectopic calcifications, as well as short lifespan and infertility. The authors named this mutant Klotho in honor of one of the Fates, the Greek goddess who weaves the thread of life [4].

The Klotho family, named Kl, has three members, including α-Kl, β-Kl and γ-Kl. In general, the word “Klotho” refers to α-Kl when no subfamily is mentioned [3,5]. The human Kl gene (α-Klotho) is located in chromosome q13.1 and consists of five exons flanked by PDS5B and STARD13 [6]. The promoter region is rich in Sp1 and cooperates with Oct-1 [7] enhancing gene expression. There are five exons covering 50 kb on chromosome 13q12 [8], and four introns in the KL coding region transcribing the mRNA of 3036, 3042, and 3042 nucleotides respectively. The Klotho gene has a functional variant, known as KL-VS (V allele), which contains three coding variants, two amino acid substitutions (F352V, C370S), and one silent mutation (K385K). Homozygosity for the V allele is associated, in humans, with reduced longevity and both heterozygotes and homozygotes have an increased risk of early-onset coronary artery disease [1,2,8].

The α-Klotho has two alternatively spliced variants, a membrane form of 1012 amino acids and a secreted form of 549 amino acids. The latter, more abundant, lacks the second internal repeat, the transmembrane domain and the intracellular domain of the membrane form. It has 1012 amino acids with a very short intracellular C-terminal sequence (10 amino acids), a transmembrane domain, and, for the most part, an extracellular portion [1]. Extracellularly, comprises two soluble domains: in its proximal part, KL1, and in its terminal part, KL2, which can be cleaved by membrane proteases (ADAM10 and ADAM17). Klotho can be released to blood, urine, and cerebrospinal fluid as a soluble form (named α-Klotho or s-Klotho). When released into the blood, s-Klotho acts as an endocrine hormone. Subsequently, s-Klotho can be generated directly through alternative RNA splicing or proteolytic cleavage [5].

There are also soluble forms of Kl (s-Kl) that can be produced not only by shedding the extracellular domain of Kl through the proteolytic activities of disintegrin and metalloproteinases 10 and 17 (ADAM10/17). However, it can also be formed by alternative splicing of the Kl gene.

The main source of Klotho is the kidney [9,10] but it is also expressed in the parathyroid glands as well as in the pancreatic β cells, blood vessels, ovary, testis, inner ear, skin peripheral blood circulating cells and central nervous system [11,12]. As stated above, the soluble forms are mainly found in body secretions such as blood, urine, and Cerebrospinal Fluid (CSF) and have endocrine, paracrine, or autocrine roles that are independent of growth factors [13]. 

Klotho-regulated pathways

KLOTHO protein is a beta-glucosidase involved in the regulation of a wide variety of physiological functions modulated by autacoids such as fibroblast growth factor-23 (FGF23; phosphate, calcium and vitamin D excretion), transforming growth factor beta (TGF-β; senescence, fibrosis), insulin growth factor (IFG-1), Wnt/-catenin (tissue fibrosis), nuclear factor (erythroid-derived 2)-like 2 (Nrf2; antioxidation and autophagy) and nuclear factor kappa B (NF-κB; free radicals and oxidative stress) (Figure 1).

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Figure 1: Comprehensive figure depicting the known hormone-, antioxidant- and antiinflammatory-based pharmacological pathways that act on the regulation of Klotho levels and the associated downstream signaling pathways with the final effects.

The extracellular domain of the transmembrane form of Klotho acts as a co-receptor of the FGF-23 receptor (FGFR). By working as, a co-receptor the affinity binding of FGF23 to FGFR1c, FGFR 3c as well as FGFR 4c can increase up to 20-fold [11,13-16]. FGF23 is synthesized mainly in the bone tissue [11] and participates in the regulation of phosphate and vitamin D balance [2,3,5,14,17]. Upon activation of FGFR, a signaling pathway is initiated through PI3K/Akt, phospholipase C γ (PLCγ), and Ras/MAPK/ERK [13,18,19].

Another pathway related to Klotho is the TGF-β signaling pathway which appears to be inhibited by this protein. TGF-β is a pleiotropic cytokine that binds to a receptor comprised of type 2 TGF-β receptor (TR2), and TβR1. TGF-β is involved in the development of cellular senescence, stem cell decline, immune impairment, and other alterations associated with aging [20-23].

IGF-I pathways have also been linked to Klotho. s-Klotho, by inhibiting IGF-I signaling and that of its receptor (IGF-IR) [24], contributes to the amelioration of aging [25]. IGF-1 is a growth factor with effects on development, growth, cell differentiation, and tissue repair [26]. Insulin/IGF-1 receptors are transmembrane tyrosine kinases that, upon ligand binding, initiate the signaling process by phosphorylation and protein binding of the insulin receptor substrate (IRS) [27]. Activation of s-Klotho connects antioxidant mechanisms through FoxO forkhead (FOXO) transcription factors. Blockade of insulin/IGF-1 pathways unlocks inhibition of these transcription factors, leading to their nuclear migration and to the expression of antioxidant enzymes, such as manganese superoxide dismutase [28].

Klotho blocks Wnt, a family of lipoproteins secreted upon Klotho’s binding to several ligands which include Wnt1, Wnt3, Wnt4, and Wnt5a [29-31]. Klotho regulates antioxidant pathways via the nuclear factor (erythroid-derived 2)-like 2 (Nfr2). This factor regulates the expression of genes involved in the protection against oxidative stress and inflammation, in addition to vital actions such as mitochondrial function preservation, protein homeostasis, autophagy regulation, and damaged protein elimination [32-34].

Additionally, Klotho blocks the signaling pathway of NFκB. This transcription factor is involved in the immune and inflammatory response as well as other cell-critical processes, such as anti-apoptotic signaling, proliferation, and oxidative stress [35-37]. Klotho carries out this modulation directly, by preventing the translocation of the NF-κB subunit Rel A (p65) from the cytoplasm to the nucleus, or by preventing the degradation of the IκB protein [38]. Thus, it has been shown that α-Klotho is able to decrease NF-κB activation and to reduce the expression of IL-8, MCP-1, RANTES, and IL-6 as well as the expression of adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) [39,40]. Moreover, the existing negative feedback between NFκB activation and the expression of Klotho should not be overlooked. Indeed, activated NFκB is capable of inhibiting Klotho, and under conditions of high inflammation, the expression and activation of NFB is higher than that of Klotho leading to the suppression of the latter [41,42].

Klotho and pathophysiology

Klotho and KL play important roles in aging-related disorders, such as chronic kidney disease [43], cardiovascular diseases [44], diabetes [45], cancer [46], and neurological disorders. A higher circulating level of Klotho is associated with a lower risk of metabolic syndrome, renal disease, and cardiovascular disease [5], and its overexpression results in increased survival [1]. On the other hand, the serum level of this protein decreases with age and is inversely related to aging phenotypes and other conditions such as renal disease, vascular calcification, cardiac hypertrophy, hypertension, fibrosis, osteopenia, pulmonary disease, neurodegeneration and, ultimately, to a higher mortality rate and shortened longevity [1]. In animal models of disease, a lack of Klotho in the brain has been associated with cognitive impairment, premature death, and synaptic loss [47]. Specifically, the human KLOTHO protein has 86% amino acids in common with murine KLOTHO. Mice deficient in Klotho develop cognitive deficits such as memory impairment and hippocampal damage.

Pharmacological regulation of Klotho levels

Several transcription factors are involved in the regulation of Klotho expression: activators, such as PAX4 [48], Sp1 and Oct-1, vitamin D, PPAR-γ [49,50], and inhibitors like FGF23 [51,52], epidermal growth factor, erythropoietin, the ras homologous gene of family A, AP-2, E-box, and NF-κB [1,53]. By operating on these regulatory factors it is feasible to pharmacologically modulate Klotho and thus achieve therapeutic benefits from this protein. We will briefly describe some of the drugs capable of regulating the Kl gene:

Hormone-based drug therapy: This has a huge potential and can be considered a modulator of Kl expression and therefore should be regarded as a first-level strategy to take advantage of Klotho’s properties. Kl expression can be modulated by numerous hormones (both at the level of the membrane and the secreted forms). For example, testosterone [54], upregulates mRNA and Kl protein levels in NRK-52E cells. Positive regulation of nuclear androgen receptor (AR) upregulates Kl levels. Flutamide, an AR antagonist drug, attenuates testosterone-modulated Kl expression. 17β-estradiol activates Kl in the hippocampus [55], while triiodothyronine increases the expression of the membrane, but not the secreted, form of Kl in 3T3-L1 adipocytes [56]. Finally, insulin enhances s-Kl production through a phosphoinositide 3-kinase (PI3K)-dependent pathway in which the ADAM 10/17 protease is involved [57].

The binding of the pleiotropic steroid hormone vitamin D to its superfamily of nuclear hormone receptor transcriptional regulators is involved in the positive regulation of Kl [58-60]. Vitamin D analogues including calcitriol, alfacalcidol, doxercalciferol, fluorocalcidol, and maxacalcitol, could have inducing effects on Kl gene expression. In this sense, calcitriol or its analog, paricalcitol, has been shown to elevate serum Kl levels in mice, independently of parathyroid hormone and calcium level alterations [58].

Inhibitors of the renin-angiotensin system: Long-term administration of Ang-II reduces the renal level expression of Kl mRNA and proteins [61] by a mechanism involving transforming growth factor-β1 (TGF-β1)- p38 MAPK-P53-SP1 and resulting in the binding of P53/SP1 to the Kl gene promoter inhibiting its transcription [61]. Thus, angiotensin receptor antagonist drugs, such as losartan and valsartan, and ACE inhibitors, such as enalapril and fosinopril, could increase Kl levels [62].

Anti-inflammatory agents: Anti-inflammatory drugs, steroidal and non-steroidal, can be effective in maintaining or even elevating Kl expression. Some inflammatory cytokines such as tumor necrosis factor α (TNFα) or the weak inducer of TNF-like apoptosis (TWEAK) reduce Kl expression [41]. The effect of TNFα appears to be mediated by a nuclear factor kappa (NF-κB) -dependent mechanism. Whereas TWEAK inhibits Kl gene expression, by inducing RelA binding to the Kl promoter, causing its deacetylation [41].

Antioxidants: In conditions where oxidative stress is evident (elevations of 8-isoprostane or hydrogen peroxide), Kl expression is inhibited [63]. In these cases, supplementation with antioxidants could be considered as another therapeutic approach. Vitamin C, vitamin E, N-acetylcysteine, melatonin, lipoic acid, and polyphenols such as curcumin, could lead to an increase in Kl [64,65]. Interestingly, the antioxidant properties of Klotho have been unintentionally used for ages. Indeed, natural alkaloids, organic compounds that contain nitrogen and constitute one of the most important effective ingredients in Chinese traditional herbal medicine, upregulate the expression of Klotho as shown by Rui, et al. [66]. These authors propose that the protective role of the herbs would be mediated by antioxidant mechanisms, mitochondrial damage improvement, cell death reduction, and inflammation inhibition. For instance, one of these alkaloids, neferine, a bisbenzylisoquinoline alkaloid, suppresses the activation of NF-κB and increases the expression of Klotho [67].

The 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors such as statins (e.g. atorvastatin, rosuvastatin, and pitavastatin) also have anti-inflammatory and antioxidant effects. Statins promote Kl gene expression by activation of the FOXO signaling pathway and inhibition of the Rho/Rho-kinase pathway [32,33], or by modulating Nrf2 and Nrf2/HO-1 [68]. Pravastatin, in a dose-dependent manner, markedly increases Klotho expression, which is responsible for the benefits of statin therapy on endothelial dysfunction and atherosclerosis [5].

Finally, other mechanisms have been suggested. For instance, a regulatory role of peroxisome proliferator-activated receptor gamma-activated receptor-γ (PPAR-γ) on Kl has been proposed [69]. Thus, PPAR-γ agonists or thiazolidinediones such as ciglitazone, troglitazone, pioglitazone and rosiglitazone, could elevate Kl levels [49]. Another proposal has been the use of the antibiotic rapamycin, which is an mTOR inhibitor that increases Klotho expression. Certainly, a delay in the onset of age-related diseases has been described after rapamycin treatment [70].

Drugs capable of controlling epigenetic modifications such as those modifying Histone Acetyltransferase (HAT) and Histone Deacetylase (HDAC) enzymes should not be overlooked in this list. Indeed, the HDAC inhibitor trichostatin-A induces a positive regulation of Kl [71] while methylation of the Kl gene promoter silences its gene expression [71]. Therefore, DNA methyltransferase inhibitors, such as azacitidine, decitabine, and zebularine, could have therapeutic potential as a Kl upregulation approach.

Klotho-induced neuroprotection

The CNS is the second most abundant organ expressing Kl after the kidneys [72]. Both Kl mRNA and protein are present in the brain parenchyma, colocalizing in neurons and oligodendrocytes. The highest amount of brain Kl was detected in the choroid plexus and is expressed by ependymal cells. Kl can be found as well in the cortex, cerebellum, hippocampus, striatum, substantia nigra, medulla, olfactory bulb, and different limbic areas, such as the thalamus, hypothalamus, and nuclei of the amygdala [73]. As for intracellular distribution, Kl has been detected in the soma and dendrites of hippocampal neurons. The roles of Kl in the nervous system are not fully understood but Kl may play an important role in neuroprotection [74,75]. Overall, Kl is necessary for healthy and normal brain function throughout life.

So far, the main conclusion obtained from the first published work in mice homozygous for a hypomorphic Klotho gene (kl/KL) was that the Klotho protein has anti-aging properties. Klotho may be part of the neuronal degeneration process [5] and is involved in the regulation of brain aging. This is suggested by the impaired cognition and abnormal brain pathology observed in Klotho mutant mice [76] and by the analysis of the genetic profile of aging changes in the white matter of the rhesus monkey brain [77]. In fact, a correlation between low Klotho levels and increased risk of stroke has been described. Klotho may also activate antiaging signaling pathways such as antioxidative and anti-inflammatory pathways.

A recent study showed a positive correlation between CSF Klotho levels with the stage of the disease. However, only one study has determined CSF Klotho levels in AD patients. This study showed a similar decrease in Klotho compared with controls [47]. How Klotho is related to AD progression in the human brain remains unknown, but studies in mice suggest that Klotho modulates N-methyl-d-aspartate receptor function and activates microglial cells to promote cognitive function [47].

Klotho depletion is associated with nerve damage and brain dysfunction [12,75], with synaptic destruction, axonal transport impairment, nerve fiber impairment, and nerve degeneration [4,76]. Mice lacking the KL gene have been shown to have learning and remembering problems, possibly due to reduced hippocampal synapses, axonal transport disorders, and hippocampal nerve damage [76]. Kl has also been shown to improve long-term potentiation (LTP) by inducing synaptic NMDA receptors and related genes such as FOS in the hippocampus and cortex, leading to learning and memory improvement [78].

Kl can bind to soluble amyloid precursor protein (APPsβ) and thus, might prevent the formation of β-amyloid structures, protecting the CNS against amyloid toxicity [79] . Semba et al. showed that CSF Kl levels were lower in AD patients than in healthy individuals, and higher in younger than in older people [80]. Existing studies with amyloidogenic mouse models have shown that overexpression of Klotho protein in the brain can ameliorate AD-like pathology and cognitive impairment as well as reverse neuronal damage. It is also known that Klotho can ameliorate Aβ accumulation in these murine models by regulating Aβ-related transporters and microglia transformation. In the early stages of AD, degradation pathways, i.e., autophagy, the Ubiquitin-Proteasome System (UPS), and Chaperone-Mediated Autophagy (CMA) are impaired. More importantly, the accumulation of β amyloid causes dysfunction in the lysosome and the Lysosomal Autophagy Pathway (LAP), leading to neuronal loss [81]. Recent studies have shown that Klotho expression and autophagy are related to the anatomical pathology of AD. Overexpression of Klotho can promote LAP in AD through activation of the beclin1 pathway [82].

Klotho displays anti-inflammatory actions under pathological conditions [83]. This is likely to take place by the blockade of the signaling pathway of NFκB. Human CNS contains a highly active NF-κB signaling system with deep implications for neurological health [84,85]. NF-κB regulates a family of microRNAs (miRNAs) which includes miRNA-9, miRNA-30b, miRNA-34a, miRNA-146a, and miRNA-155. These miRNAs, in addition to having a general role in immunity, inflammation, and gene function in the CNS [86-88], are involved in the neurodegenerative pathogenesis of AD. Indeed, these miRNAs have been found to be significantly upregulated in this condition [89,90]. In line with these findings, overexpression of α-Klotho in the mouse choroid plexus ameliorates behavioral shortage and increases the number of living neurons upon brain hypoperfusion. All this is accompanied by a decrease in the production of proinflammatory cytokines and activation of astrocytes and microglia [43]. Oxidative stress generates mitochondrial dysfunction, impairs DNA repair, and causes cell damage. All the latter are part of the pathogenesis of neurodegenerative diseases, such as AD [91]. Thus, Klotho activates Nrf2 in a way that protects from renal, cardiovascular, and neurological disease [92,93].

Other pathways, such as the Insulin/IGF pathway, have been related to Klotho in the CNS. Insulin/IGF signaling promotes olfactory associative learning [94,95] and is involved in CNS plasticity in the hypothalamus, hippocampus, olfactory bulb, and other brain areas [27,96]. Alterations in the insulin signaling cascade underlie cognitive impairment and the development of several neurodegenerative diseases. Blockade of IGF-I receptors has been associated with cerebral amyloidosis and accumulation of hyperphosphorylated tau protein. Also, cognitive impairment and other neuropathological changes are typical of AD [97]. In addition, the blockade of IGF-I signaling induced by s-Klotho has been shown to increase resistance to oxidative stress, thereby improving survival rates [28].

Another target pathway is Wnt. Wnt is expressed in various CNS territories such as radial glia, oligodendrocytes, microglia, astrocytes, and neurons [98-100] where it regulates neuronal patterning, stem cell proliferation, and neurogenesis [101-103]. Wnt, by binding to the so-called Frizzled receptors, engages in systemic physiological processes such as cell differentiation, polarity, and migration [101,104,105]. Wnt also protects against β-amyloid peptide (Aβ) neurotoxicity. This seems to be due to the role Wnt takes in glycogen synthase kinase-3 β (GSK-3 β)-catalyzed Tau phosphorylation. A hyperactivation of Wnt is associated with the generation of embryonic degenerative abnormalities and tissue fibrosis [29,105-107]. Wnt dysfunction may be involved in aging and has been associated with memory impairment [98,99,101,103,105-107] and in learning and memory processes [106-108]. In Klotho-deficient mice, excess Wnt activation promotes cellular senescence and has a negative impact on stem cell survival [109].

With regard to the relationship between FGF23 and Klotho, elevated levels of FGF23 are associated with Klotho deficiency [4]. Thus, the production of FGF23 is inversely related to the serum concentration of Klotho. This has been confirmed in the CNS as well. Indeed, a higher serum FGF23 concentration is associated with an increased risk of incident dementia and AD [110,111], perhaps due to the existence of cardiovascular risk factors or vascular evidence of brain injury or to an FGF23-dependent reduction in vitamin D levels, which is known to be a predictor of cognitive impairment in adults.

Finally, it should be emphasized that there is a serious lack of human studies focused on Klotho’s expression and functionality in the central nervous system. This is striking and therefore it is urgent to address this research, the results of which may be more than promising.

In conclusion, our understanding of Klotho and its function related to neurodegenerative disease progression is far from complete. However, it appears clear that Klotho offers protective roles against nervous system damage by interfering with numerous pathways. At present, one of the main limitations we still suffer from is the lack of specific klotho-modulating drugs. So, the effects on klotho-mediated protection of existing drugs should be further investigated.

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