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Klotho, The Golden Thread of Life, & Glycoimmunology

Updated: Dec 2, 2023


In ancient Greek mythology, Clotho, one of the three Fates, spins the thread of human life. Clotho from Greek Klōthō, literally means "the spinner," from klōthein "to spin".

We believe the life extending properties of the gene Klotho is an integral part of Glycoimmunology, which is the study of how glycans (sugar chains) control innate and adaptive immune responses.


In biology, these golden threads that are spun may be represented by sugar chains, which are involved with every aspect our anatomy, holding our health together, and giving us life.


Klotho helps spin the golden thread of life by assisting with how sugar chains are weaved onto the outer surface of the cell. Klotho spins and weaves the sugar basket, so to speak.


What is Klotho?


Klotho, a gene that has been extensively studied for its role in extending lifespan, has a fascinating connection to Greek mythology. In Greek mythology, there are three goddesses known as the Fates - Klotho, Lachesis, and Atropos - who control the thread of life (Ullah & Sun, 2018). Among them, Klotho is responsible for spinning and controlling the thread of life (Ullah & Sun, 2018). This connection between the gene and the mythological figure highlights the significance of Klotho in the understanding of aging and longevity.


The Klotho gene was discovered in 1997 and named after the goddess Klotho in ancient Greek mythology (Wei et al., 2021). It encodes a protein that regulates multiple functions in the body (Moos et al., 2020). The protein acts as an obligatory co-receptor, binding and activating critical fibroblast growth factor activity (Moos et al., 2020). When the Klotho pathways go awry, oxidative stress and mitochondrial dysfunction can occur, leading to age-related chronic disorders (Moos et al., 2020). This suggests that Klotho plays a crucial role in maintaining cellular health and preventing age-related diseases.


Studies have shown that Klotho is involved in various biological activities and has protective effects on different systems in the body. For example, Klotho has been found to protect chondrocyte viability in osteoarthritis (Wei et al., 2021). It does so by activating the FOXO1/3 pathway, which promotes cell survival (Wei et al., 2021). Additionally, Klotho has been implicated in cardiovascular and renal diseases, where its deficiency can contribute to the development of these conditions (Maltese & Karalliedde, 2012). On the other hand, overexpression of Klotho has been shown to prolong lifespan (Jawiarczyk-Przybyłowska et al., 2015).


The name "Klotho" itself reflects the high expectations associated with the gene. In Greek mythology, Klotho was responsible for spinning the thread of human life, symbolizing the potential for understanding and manipulating the aging process (Biggar et al., 2014). The discovery of the Klotho gene has opened up new avenues for research into aging and age-related diseases.


In conclusion, the connection between the Klotho gene and Greek mythology adds an intriguing dimension to the study of aging and longevity. The gene, named after the goddess Klotho, plays a crucial role in regulating various biological processes and has been implicated in age-related diseases. Understanding the mechanisms by which Klotho influences aging and lifespan may provide valuable insights into developing interventions for promoting healthy aging.


Klotho & Glycoimmunology


Glycoimmunology is a field of study that focuses on the role of glycans in immune responses. Glycans, which are complex sugar molecules, play a crucial role in various immune processes, including cell-cell interactions, signaling, and inflammation (Vanhooren et al., 2011). One specific protein that has been implicated in glycoimmunology is Klotho.


Klotho is a transmembrane protein that is primarily expressed in the kidneys and brain, but it is also found in other tissues, including immune organs (Kiela, 2009). It has been shown to have anti-aging effects and is involved in various physiological processes, including phosphate homeostasis, calcium metabolism, and vitamin D signaling (Kiela, 2009). Several studies have investigated the role of Klotho in immune responses. For example, a study by used a mouse model to analyze immune responses in Acinetobacter baumannii-infected Klotho knockout mice (Satoh et al., 2020). The study found that aged Klotho knockout mice had higher mortality rates, increased bacterial burdens, and more severe lung injury compared to control mice. This suggests that Klotho plays a protective role in the immune response to bacterial infections. Another study by explored the effects of vitamin E on Klotho expression and immune functions in dendritic cells (DCs) (Xuan et al., 2016). The researchers found that vitamin E treatment increased Klotho expression in DCs and enhanced their maturation, reactive oxygen species production, and migration. This suggests that Klotho may play a role in modulating DC functions and immune responses. Furthermore, demonstrated that FGF23, a hormone involved in phosphate homeostasis, interacts with Klotho in the regulation of immune responses (Farrow et al., 2009). FGF23 signaling occurs through the formation of a receptor complex between FGF23 and Klotho, which activates downstream signaling pathways. Studies have shown that FGF23-Klotho interactions are important for maintaining phosphate homeostasis and that disruption of this interaction can lead to hyperphosphatemia. In addition to its role in immune responses, Klotho has also been implicated in other physiological processes, such as neuroinflammation. A study by demonstrated that Klotho acts as a signal transducer between pro-survival and pro-apoptotic pathways in hippocampal neuronal cells during neuroinflammatory challenges (Rusinek et al., 2020). This suggests that Klotho may play a role in regulating neuroinflammatory processes. Overall, these studies highlight the importance of Klotho in immune responses and its potential role in glycoimmunology. Further research is needed to fully understand the mechanisms underlying the interactions between Klotho, glycans, and immune responses. However, these findings provide valuable insights into the role of Klotho in immune regulation and its potential as a therapeutic target for immune-related disorders.


Klotho & Mannose Receptors


Klotho, a protein encoded by the Klotho gene, has been found to have various impacts on different receptors and signaling pathways. One area of interest is the interaction between Klotho and Mannose Receptors (MRs). The Mannose Receptor is a C-type lectin receptor that plays a crucial role in the immune response and is involved in the recognition and clearance of pathogens (Nakai & Tsuruta, 2021).


One study suggests that Klotho may have an inhibitory effect on insulin/IGF-1 activity. Secreted Klotho has been shown to inhibit insulin and IGF-1-induced autophosphorylation of insulin receptor and IGF-1 receptor in cultured cells (Kuro-o, 2009). This suggests that Klotho may alter the internalization and cell surface abundance of insulin/IGF-1 receptors by modifying their glycans. This finding indicates a potential regulatory role of Klotho in the insulin/IGF-1 signaling pathway.


Furthermore, Klotho has been implicated in the pathogenesis of psoriasis. Macrophages, which express MRs, Klotho, and inducible nitric oxide synthase (iNOS), are found in the skin lesions of psoriasis patients (Nakai & Tsuruta, 2021). This suggests that macrophages in psoriasis may not simply produce nitric oxide by activating iNOS but may also be involved in the production of reactive oxygen species (ROS) and the regulation of MRs and Klotho. The exact role of Klotho in psoriasis and its interaction with MRs in this context require further investigation.


In addition to its role in the immune response, Klotho has also been implicated in neuroprotection and cognitive function. The neuroprotective effects of Klotho are not fully understood, but it has been suggested that Klotho may enhance cognition and protect against age- and neurodegeneration-related cognitive dysfunction (Hanson et al., 2021). The specific neuronal receptor for Klotho and the signaling pathways activated by Klotho in the brain are still unknown. Further research is needed to elucidate the molecular and cellular mechanisms underlying the neuroprotective properties of Klotho.


Overall, the available evidence suggests that Klotho may impact Mannose Receptors through its regulatory effects on insulin/IGF-1 signaling and its potential involvement in the pathogenesis of psoriasis. However, the exact mechanisms by which Klotho interacts with MRs and the functional consequences of this interaction require further investigation.


Mannose Receptors & Immune Function


Mannose receptors play a crucial role in the immune system by functioning as high capacity and broad specificity antigen receptors in dendritic cells (Engering et al., 1997). These receptors are involved in the uptake of certain microorganisms, such as mycobacteria, enterobacteria, and fungi, and are thought to initiate immune responses against a diversity of pathogens (Engering et al., 1997). The mannose receptor also plays a central role in coordinating the innate and adaptive immune responses by enhancing the uptake and processing of soluble glycoconjugates released from pathogens for presentation to T cells (Feinberg et al., 2000). Additionally, the mannose receptor regulates the levels of endogenous proteins bearing high mannose oligosaccharides, such as lysosomal enzymes and tissue plasminogen activator, which are released from tissues into the blood in response to pathological events (Feinberg et al., 2000).


The mannose receptor is considered a pattern recognition receptor (PRR) that recognizes common structural and molecular motifs present on microbial surfaces (Lee et al., 2003). It is expressed on subsets of macrophages and is involved in phagocytosis of mannose-bearing microbes, including Candida albicans (Lee et al., 2003). In vitro experiments have shown that the mannose receptor enhances the antifungal response by macrophages (Lee et al., 2003). Moreover, mannose receptors allow macrophages and dendritic cells to bind and engulf pathogens with surface mannose residues, contributing to innate immunity (Lin & Kasko, 2013). C-type lectins, including the mannose receptor, act as pattern recognition receptors and are able to bind to pathogens, activate immunity, and mediate cell-cell interactions during immune responses (Coelho et al., 2010).


The mannose receptor is also involved in antigen presentation and phagocytosis. It has been shown to play a role in cytokine-stimulated antigen presentation in both Th1 (cellular immunity) and Th2 (humoral immunity) immune responses (Raveh et al., 1998). Mannosylation of protein-based virus-like particles enhances their uptake by antigen-presenting cells, leading to improved immune responses (Ashrafzadeh et al., 2014). Furthermore, the mannose receptor is expressed by microglia, the brain resident macrophages, and its expression and activity can be modulated by proinflammatory and anti-inflammatory cytokines (Zimmer et al., 2003).


In conclusion, mannose receptors are important components of the immune system, functioning as antigen receptors, pattern recognition receptors, and mediators of antigen presentation and phagocytosis. They play a crucial role in initiating immune responses against a variety of microorganisms and coordinating the innate and adaptive immune responses. The mannose receptor is expressed on dendritic cells, macrophages, and microglia, and its activity can be modulated by cytokines. Understanding the role of mannose receptors in the immune system can provide insights into the development of targeted therapies for infectious diseases.


Klotho & Life Extension


Klotho is a protein that has been extensively studied in relation to aging and life extension. It has been found that secreted Klotho can inhibit TGF-β1 activity, which may counteract tissue fibrosis and cancer metastasis (Kuro-o, 2011). In fact, injecting secreted Klotho has been shown to prevent renal fibrosis and metastasis of human cancer xenografts in mice (Kuro-o, 2011). These activities of secreted Klotho may contribute to life span extension, as overexpression of Klotho in mice has been shown to extend their life span (Kuro-o, 2011).


Furthermore, Klotho has been associated with oxidative stress regulation. Single nucleotide polymorphisms in the human KLOTHO gene have been found to be associated with longevity and age-related diseases, suggesting that Klotho plays a role in aging regulation in humans (Clark et al., 2005). Increased resistance to oxidative stress is also associated with increased longevity in various species (Clark et al., 2005).


Klotho has also been implicated in neurodegenerative disorders. Overexpression of Klotho in mice has been shown to extend their lifespan, while Klotho deficiency or silencing of the Klotho gene leads to accelerated aging and a shorter life span (Torbus-Paluszczak et al., 2018). Klotho is highly expressed in the kidneys, the choroid plexus, and neurons, and its overexpression has been associated with life extension (Torbus-Paluszczak et al., 2018).


In addition, Klotho has been found to regulate the Na+/K+ ATPase, which is involved in maintaining cellular ion balance. Klotho deficiency in mice accelerates aging and leads to death within a few months, while Klotho overexpression extends life span (Sopjani et al., 2011).


Furthermore, Klotho deficiency has been linked to salt-sensitive hypertension and inflammation. Insertional mutation of the mouse Klotho gene resulted in premature aging phenotypes and shortened lifespan, while overexpression of the gene extended lifespan and rescued aging disorders (Zhou et al., 2015).


Overall, the research suggests that Klotho plays a crucial role in the aging process and life extension. Its ability to inhibit TGF-β1 activity, regulate oxidative stress, and modulate various physiological processes may contribute to its effects on longevity. Further research is needed to fully understand the mechanisms by which Klotho influences aging and life span.


Klotho & Stem Cells


Klotho is a protein that plays a significant role in stem cell function and aging (Yu & Li, 2020). Several studies have investigated the relationship between Klotho and stem cells, providing insights into the mechanisms by which Klotho affects stem cell fate and function.


One study by Yu & Li (2020) explored the role of Klotho in mediating vascular calcification. The authors proposed that Klotho deficiency alters the functional features of stem cells, leading to impaired differentiation potential, cellular senescence, and apoptosis. Klotho deficiency was also found to activate calcification-associated signaling pathways in stem cells, such as the TGF-β1 and Wnt pathways, which are associated with the osteogenic differentiation potential of vascular cells.


Another study by Bian et al. (2015) investigated the relationship between Klotho, stem cells, and aging. The authors found that Klotho deficiency activates Wnt expression and activity, contributing to senescence and depletion of stem cells. On the other hand, the Klotho protein was shown to suppress Wnt signaling, inhibit cell senescence, and preserve stem cells. This suggests that Klotho plays a crucial role in regulating stem cell function and may be involved in the cellular and molecular mechanisms of aging and disease.


The study by Hu & Moe (2012) focused on the potential of Klotho as a biomarker and therapy for acute kidney injury. The authors found that Klotho acts as a secreted Wnt antagonist, blocking Wnt binding to its membrane receptor and inhibiting its biological activity. Klotho deficiency was associated with high levels of cell senescence and stem cell depletion in renal tissues, which were reversed by Klotho protein overexpression. This suggests that Klotho may have a protective effect on stem cells and play a role in kidney injury and fibrosis.


Furthermore, a study by Liu et al. (2007) investigated the role of Klotho in a mammalian model of accelerated aging. The authors found that Klotho deficiency resulted in a diminished number of transient amplifying cells, which are induced by acute wounding. This suggests that Klotho is involved in the regulation of stem cell populations and may play a role in tissue regeneration and repair.


Overall, these studies provide evidence for the important role of Klotho in regulating stem cell fate and function. Klotho deficiency has been associated with impaired differentiation potential, cellular senescence, and depletion of stem cells. On the other hand, Klotho has been shown to suppress Wnt signaling, inhibit cell senescence, and preserve stem cells. Further research is needed to fully understand the mechanisms by which Klotho affects stem cells and its potential implications for aging and disease.


Klotho & Beta-Glucosidase


Klotho is related to beta-glucosidases. Beta-glucosidase is an enzyme that plays a crucial role in various biological processes, including the hydrolysis of cellulose (Sørensen et al., 2013). It is widely available in animals, plants, and microorganisms (Binh et al., 2022). The activity of beta-glucosidase is influenced by factors such as substrate specificity and glycosylation (Sørensen et al., 2013; Hayes et al., 2016). Glycosylation, the process of attaching sugar molecules to proteins, strongly affects the function of immunoglobulins and the immune system in general (Hayes et al., 2016). Changes in glycosylation of immunoglobulin G (IgG) have been associated with aging and inflammation (Hayes et al., 2016).


In the context of glycoimmunology, the study of the relationship between glycans and the immune system, understanding the role of beta-glucosidase and glycosylation is crucial. Glycans, which are complex sugar molecules, have been identified as novel biomarkers of chronological and biological ages (Krištić et al., 2013). Longitudinal studies are needed to determine whether changes in glycosylation of IgG contribute to aging by promoting inflammation (Krištić et al., 2013).


Furthermore, beta-glucosidase has been implicated in drug delivery systems and cytotoxicity in colon cancer cells (Arafa, 2009).


Beta-glucosidase and glycosylation play important roles in various biological processes, including cellulose hydrolysis, aging, inflammation, drug delivery, and industrial applications. Further research is needed to fully understand the mechanisms and implications of beta-glucosidase activity and glycosylation in these contexts.


Beta-Glucosidase & Innate Immunity


Beta-glucosidases are enzymes that play a crucial role in various biological processes, including the innate immune system. Beta-defensins, small secreted peptides encoded by genes in different clusters, are important components of the innate immune system (Hollox, 2008). They act directly to kill pathogens and signal to other components of the inflammatory response. Beta-glucans, which are carbohydrates found in yeast cell walls, can activate the innate immune system by binding to specific receptors and activating mediators of the immune response (Zent et al., 2015). Beta-glucans act as pathogen-associated molecular patterns (PAMPs) and bind to receptors such as dectin-1, inducing both adaptive and innate immunity (Ikewaki et al., 2022).


The innate immune system is involved in the destruction of beta cells in type 1 diabetes and after beta cell transplantation (Torren et al., 2015). In type 2 diabetes, metabolic stress activates the innate immune system, leading to chronic inflammation and beta-cell dysfunction and death (Nunemaker, 2016; Böni-Schnetzler & Donath, 2013). The activation of the innate immune system in both types of diabetes involves the release of cytokines and the recruitment of immune cells to the islets (Nunemaker, 2016; Böni-Schnetzler & Donath, 2013). Increased numbers of macrophages are present in and around islets in patients with type 2 diabetes (Böni-Schnetzler & Donath, 2013).


Beta-glucosidases also have relevance in other biological processes. They are involved in the decomposition of organic polymers, such as polysaccharides, in aquatic ecosystems (Zaccone & Caruso, 2019). These enzymes play a role in the biogeochemical and nutrient cycles by breaking down organic matter and supporting microbial growth (Zaccone & Caruso, 2019). Additionally, beta-glucosidases have been studied for their industrial use in the hydrolysis of lignocellulosic materials (Sørensen et al., 2013). They have a wide specificity for beta-D-glucosides and can hydrolyze various substrates (Sørensen et al., 2013).


In conclusion, beta-glucosidases are enzymes that have diverse roles in biological processes, including their involvement in the innate immune system. They are important in the activation of the immune response, the decomposition of organic polymers, and the industrial use of lignocellulosic materials. Understanding the functions and mechanisms of beta-glucosidases can provide insights into various biological and medical applications.


Klotho & Inflammation


Klotho is a protein that has been found to play a role in inflammation and cytokine regulation. Several studies have investigated the relationship between Klotho and inflammation, and have provided insights into the mechanisms by which Klotho modulates inflammatory responses.


One study by Zhao et al. (2011) found that Klotho depletion contributes to increased inflammation in the kidney of diabetic mice. The researchers observed that Klotho inhibited p38 kinase and specifically blocked the phosphorylation of RelA serine 536, a key step in the activation of NF-κB. This resulted in the suppression of NF-κB-dependent promoters of multiple cytokines, indicating that Klotho serves as an anti-inflammatory modulator by regulating the production of inflammatory cytokines.


Another study by Richter & Faul (2018) discussed the actions of FGF23, a hormone that interacts with Klotho, on target tissues. The authors highlighted that FGF23 can induce the expression of inflammatory cytokines in the liver and inhibit neutrophil recruitment. They also discussed the potential inhibitory effects of soluble Klotho on FGF23-mediated signaling, suggesting that Klotho may have tissue-protective functions.


Fitzpatrick et al. (2018) investigated the role of FGF-23 in innate immune responses. They found that inflammatory cytokines can stimulate the transcription of FGF-23 in bone and induce the expression of FGF-23 and α-Klotho in macrophages. This suggests that FGF-23 may play a role in regulating innate immunity through multiple mechanisms.


Banerjee et al. (2013) reported that Klotho regulates inflammation by suppressing NF-κB activation in response to inflammatory stimuli. They found that Klotho inhibits the phosphorylation of RelA serine 536 and its transactivation, leading to the suppression of NF-κB-dependent inflammatory responses.


Huang et al. (2017) demonstrated that Klotho suppresses the inflammatory responses in aging endotoxemic mice. They showed that Klotho can suppress the expression of adhesion molecules and pro-inflammatory cytokines, suggesting that Klotho negatively modulates inflammation.


These studies collectively suggest that Klotho plays a role in modulating inflammation and cytokine production. It inhibits NF-κB activation and the expression of inflammatory cytokines, thereby exerting anti-inflammatory effects. Klotho may serve as a potential therapeutic target for the treatment of inflammatory diseases.


Klotho & Brain Function


Klotho, a protein that plays a role in various physiological processes, has been found to have implications for brain health and function. Several studies have explored the relationship between Klotho and neurodegenerative disorders, cognitive impairment, and myelination in the brain.


One study focused on the role of Klotho in neurodegenerative disorders, particularly multiple sclerosis (Torbus-Paluszczak et al., 2018). The authors highlighted the neuroprotective function of Klotho and its involvement in calcium-phosphate metabolism, remyelination, and cognitive processes. They emphasized the potential therapeutic implications of Klotho in the treatment of neurodegenerative diseases.


Another study investigated the cognitive impairment observed in mice with a mutation in the Klotho gene (Nagai et al., 2002). The researchers found that Klotho mutant mice exhibited neural degeneration and reduced levels of neurofilaments in the spinal cords. They suggested that Klotho may be involved in the regulation of brain aging and cognitive function.


The neuroprotective effects of α-klotho in age- and neurodegeneration-related cognitive dysfunction were explored in a review article (Hanson et al., 2021). The authors discussed the molecular and cellular pathways through which α-klotho mediates its cognitive-enhancing properties. They raised questions about the specific form of α-klotho involved, the neuronal receptor for α-klotho, and the signaling pathways activated by α-klotho in the brain. They also highlighted the potential of α-klotho as a therapeutic target for age- and neurodegeneration-associated cognitive dysfunction.


The expression of Klotho protein in various tissues, including the brain, was examined in a comparative study (Li et al., 2004). The researchers found that Klotho protein was highly expressed in the brain, kidney, testis, and ovary. This study provided evidence of Klotho protein expression in the brain, supporting its potential role in brain function.


The impact of Klotho on myelination in the central nervous system (CNS) was investigated in another study (Chen et al., 2013). The researchers observed downregulation of Klotho in aged brain white matter and suggested that reduced Klotho levels may contribute to myelin damage and age-related cognitive decline. They proposed that increasing Klotho levels could protect myelin integrity and prevent myelin degeneration in the aged brain. This study highlighted the potential therapeutic implications of Klotho in diseases involving myelin abnormalities, such as multiple sclerosis.


Overall, these studies provide evidence for the involvement of Klotho in brain health and function. They suggest that Klotho may have neuroprotective effects, influence cognitive function, and play a role in myelination in the CNS. Further research is needed to fully understand the molecular mechanisms underlying these effects and to explore the potential therapeutic applications of Klotho in neurodegenerative disorders and cognitive dysfunction.


Klotho & Nervous System


Klotho is a protein that plays a significant role in various aspects of the nervous system. It has been implicated in neurodegenerative disorders, cognitive impairment, brain aging, and neuroprotection (Torbus-Paluszczak et al., 2018; Nagai et al., 2002; Neyra et al., 2020; Dubal et al., 2015). Klotho is expressed in the brain, kidney, reproductive organs, pituitary gland, and parathyroid gland (Li et al., 2004). In the brain, Klotho is involved in calcium-phosphate metabolism, remyelination, and cognitive processes (Torbus-Paluszczak et al., 2018).


Studies have shown that Klotho-deficient mice exhibit central nervous system lesions, including hypomyelination, synaptic loss, and behavioral impairments such as dementia and cognitive deficits (Neyra et al., 2020). Klotho deficiency in the brain also impairs the blood-brain barrier and promotes immune-mediated central nervous system disorders (Neyra et al., 2020). Furthermore, overexpression of Klotho has been shown to enhance cognition and synaptic plasticity, suggesting its potential as a therapeutic target for neurodegenerative diseases such as Alzheimer's disease (Dubal et al., 2015).


The neuroprotective function of Klotho has been observed in various studies. It has been shown to protect neurons from ischemic injury and inhibit neuronal pyroptosis, a form of cell death associated with inflammation (Liu et al., 2023). Klotho has also been found to prevent mortality and enhance cognition in transgenic mouse models of Alzheimer's disease (Dubal et al., 2015). Additionally, Klotho has been implicated in the regulation of oxidative stress in the brain, which is associated with cognitive impairment (Nagai et al., 2002).


The role of Klotho in the nervous system extends beyond neurodegenerative disorders. It has been suggested that Klotho plays a neuroprotective role by regulating the redox system and increasing resistance to oxidative stress in neuronal cells (Naeeni et al., 2023). Furthermore, Klotho has been associated with longevity and susceptibility to multiple complex disorders, including depression and stroke (Pavlatou et al., 2016). It has been shown to influence the aging process and is activated by soluble amyloid precursor protein, which may have implications for neurodegenerative diseases (Pavlatou et al., 2016).


In conclusion, Klotho is a protein that plays a crucial role in the nervous system. It is involved in various processes, including calcium-phosphate metabolism, remyelination, cognition, neuroprotection, and the regulation of oxidative stress. Klotho deficiency has been associated with neurodegenerative disorders, cognitive impairment, and behavioral deficits. On the other hand, overexpression of Klotho has been shown to enhance cognition and synaptic plasticity. Further research is needed to fully understand the mechanisms underlying the role of Klotho in the nervous system and its potential as a therapeutic target for neurodegenerative diseases.


Klotho & Myelin


Klotho, an anti-aging protein, has been found to play a role in myelination in the central nervous system (CNS) (Chen et al., 2013). It has been hypothesized that Klotho secreted by the choroid plexus may protect myelin integrity and prevent myelin degeneration in the aging brain (Chen et al., 2013). Klotho has also been shown to enhance oligodendrocyte maturation and myelination in the CNS (Chen et al., 2013). It is believed that Klotho may function as a humoral factor secreted by neurons or the choroid plexus to promote myelination in neurodevelopment and have a regulatory role in maintaining or supporting oligodendrocyte function in the adult CNS (Chen et al., 2014).


The effects of Klotho on myelination may be mediated through various signaling pathways. One study suggests that Klotho may inhibit the Wnt/β-catenin pathway, which delays the development of myelinating oligodendrocytes (Chen et al., 2013). Another study proposes that Klotho may stimulate oligodendrocyte maturation through the Wnt or insulin/IGF signaling pathways, in addition to the FGF and NGF pathways (Chen et al., 2013). Furthermore, Klotho has been shown to accelerate remyelination in a mouse model of demyelination, suggesting its potential role in promoting myelin repair (Moos et al., 2020).


The role of Klotho in myelination is not limited to normal development and aging. It has also been implicated in neurodegenerative disorders, including multiple sclerosis (MS) (Torbus-Paluszczak et al., 2018). Klotho has been shown to have a neuroprotective function and may be involved in the calcium-phosphate metabolism and remyelination processes (Torbus-Paluszczak et al., 2018). In fact, research efforts are being directed towards developing MS treatments that promote remyelination and stimulate myelin repair, with a focus on Klotho (Moos et al., 2020).


Overall, the evidence suggests that Klotho plays a crucial role in myelination in the CNS. It may protect myelin integrity, enhance oligodendrocyte maturation, and promote myelin repair. Further research is needed to fully understand the mechanisms by which Klotho influences myelination and its potential therapeutic implications for neurodegenerative disorders.


Klotho & Cardiovascular Heart Health


Klotho, a protein primarily expressed in the kidneys, has been found to have potential cardioprotective effects. Several studies have investigated the relationship between Klotho and heart health. One study by Xie et al. (2012) demonstrated that soluble Klotho can downregulate TRPC6 channels in the mouse heart, potentially preventing pathological cardiac hypertrophy (Xie et al., 2012). Another study by Olejnik et al. (2020) found that compensatory production of Klotho after myocardial infarction may protect against left ventricular hypertrophy and additional heart failures (Olejnik et al., 2020).


In addition, Zhu et al. (2022) found that low Klotho concentration is associated with an increased risk of cardiovascular death or heart failure hospitalization in patients with stable ischemic heart disease (Zhu et al., 2022). These findings suggest that Klotho may play a role in the pathophysiology of heart disease.


The interaction between Klotho and other factors involved in heart health has also been investigated. (2020) reviewed the link between Klotho and fibroblast growth factor 23 (FGF23) in different organs, including the heart, and suggested that targeting this pathway may help prevent complications associated with chronic kidney disease (Muñoz-Castañeda et al., 2020; . Silva et al., 2019) explored the potential use of plasmatic Klotho and FGF23 as markers for cardiac disease in patients with chronic kidney disease (Silva et al., 2019). These studies highlight the complex interplay between Klotho, FGF23, and cardiac health.


In terms of mechanisms, (2020) demonstrated that Klotho administration can prevent calcium mishandling in a mouse model of uremic cardiomyopathy (Navarro-García et al., 2020). Additionally, Xu et al. (2022) found that low levels of soluble α-Klotho are associated with congestive heart failure and myocardial infarction in humans (Xu et al., 2022). These findings suggest that Klotho may have a direct impact on cardiac function through its effects on calcium regulation.


In conclusion, the available evidence suggests that Klotho plays a role in heart health and disease. It has been shown to have cardioprotective effects, potentially preventing pathological cardiac hypertrophy and protecting against left ventricular hypertrophy and heart failure. However, the exact mechanisms underlying these effects are still being elucidated. Further research is needed to fully understand the role of Klotho in the heart and its potential as a therapeutic target for cardiovascular disease.


Klotho & Gut Health


Klotho, a protein predominantly produced in the kidney, has been the subject of research due to its potential role in aging and age-related diseases (Kim et al., 2015). While the understanding of the relationship between Klotho and gut health is still in its early stages, there are emerging connections between Klotho, the gut microbiota, and various aspects of gut health.


One potential link between Klotho and gut health is through the modulation of cell stress responses via the processing of dietary (poly)phenolic acids, which are potent Nrf2 agonists (Buchanan et al., 2020). The relationship between the gut microbiota and Nrf2 expression is an emerging therapeutic axis for the treatment of age-related diseases, which may also be relevant to Klotho.


Furthermore, the gut microbiota has been implicated in the regulation of thermogenesis and browning of adipose tissue, which are important factors in maintaining a healthy metabolism (Zhou et al., 2019; Reynés et al., 2019). In a mouse model resistant to diet-induced obesity, the alteration in gut microbiota profile induced by a high-fat diet was reduced, suggesting a potential role of the microbiota in modulating thermogenic capacity (Reynés et al., 2019). This finding is relevant to Klotho, as the β-Klotho knockout mouse model, which exhibits enhanced energy expenditure and brown adipose tissue activity, showed a similar gut microbiota profile to wild-type mice (Reynés et al., 2019).


Additionally, bile acids, which are metabolized by the gut microbiota, have been implicated in the regulation of gut barrier integrity and the release of Fibroblast Growth Factor 19 (FGF19) and β-Klotho (Meroni et al., 2019). Both FGF19 and β-Klotho can downregulate bile acid synthesis in the liver, suggesting a potential role of the gut microbiota in modulating Klotho levels (Meroni et al., 2019).


Overall, while the understanding of the relationship between Klotho and gut health is still limited, there are emerging connections between Klotho, the gut microbiota, and various aspects of gut health. Further research is needed to elucidate the mechanisms underlying these connections and to explore the potential therapeutic implications for age-related diseases.


Klotho & The Extracellular Matrix


Klotho is a protein that plays a crucial role in various physiological processes, including the regulation of the extracellular matrix (ECM) (Vervloet & Cozzolino, 2017). The ECM is a complex network of proteins and carbohydrates that provides structural support to cells and tissues (Vervloet & Cozzolino, 2017). Klotho has been shown to protect against renal fibrosis by inhibiting Wnt signaling, which is involved in the deposition of ECM components (Satoh et al., 2012). Additionally, Klotho deficiency is a key feature of chronic kidney disease (CKD), which is characterized by the accumulation of ECM and vascular calcification (Vervloet & Cozzolino, 2017).


One of the mechanisms by which Klotho regulates the ECM is through its interaction with fibroblast growth factor (FGF) receptors. Both the membrane-bound and soluble forms of Klotho can bind to FGF receptors and increase their affinity for FGF23 (Cha et al., 2009; . FGF23 is a hormone that regulates phosphate and vitamin D metabolism, and dysregulation of FGF23 signaling can lead to abnormal ECM deposition (Scanni et al., 2014). Furthermore, Klotho has been shown to modulate the activity of Wnt proteins, which are involved in ECM mineralization (Satoh et al., 2012).


In addition to its direct effects on the ECM, Klotho also plays a role in the regulation of ion channels, including those involved in potassium excretion (Cha et al., 2009). Disturbances in potassium homeostasis can lead to alterations in ECM composition and function (Cha et al., 2009). Moreover, Klotho has been implicated in the adaptive response to nutritional challenges, which can affect ECM remodeling (Martínez-Garza et al., 2019).


Overall, Klotho is a critical regulator of the ECM, with its deficiency being associated with pathological conditions such as renal fibrosis and vascular calcification. By interacting with FGF receptors, modulating Wnt signaling, and regulating ion channels, Klotho influences the composition and function of the ECM. Further research is needed to fully understand the molecular mechanisms underlying the role of Klotho in ECM regulation and its potential therapeutic implications.


The Role of Klotho in Autoimmune Disorders


Autoimmune disorders are characterized by an abnormal immune response against self-antigens, leading to chronic inflammation and tissue damage. The pathogenesis of autoimmune diseases involves a complex interplay between genetic and environmental factors. Recent research has highlighted the potential role of Klotho, a protein with diverse functions, in the development and progression of autoimmune disorders.


Klotho and Neurodegenerative Disorders:


Klotho has been extensively studied in the context of neurodegenerative disorders, such as multiple sclerosis (MS) (Torbus-Paluszczak et al., 2018). It has been shown to play a neuroprotective role and is involved in calcium-phosphate metabolism, remyelination, and cognitive processes (Torbus-Paluszczak et al., 2018). The neuroprotective function of Klotho has been demonstrated in animal models of MS, suggesting its potential as a therapeutic target for autoimmune neurodegenerative diseases (Torbus-Paluszczak et al., 2018).


Klotho and Vascular Calcification:


Vascular calcification is a common complication of chronic kidney disease (CKD) and is associated with increased cardiovascular morbidity and mortality. Studies have shown that Klotho deficiency contributes to vascular calcification in CKD (Hu et al., 2011). CKD patients and animals with end-stage CKD exhibit reduced Klotho levels, indicating a state of "pan deficiency" of Klotho in CKD (Hu et al., 2011). Supplementation of soluble Klotho has been suggested as a potential therapeutic approach to prevent or attenuate vascular calcification in CKD patients (Neyra & Hu, 2017).


Klotho and Autophagy:


Autophagy is a cellular process involved in the degradation and recycling of damaged organelles and proteins. Dysregulation of autophagy has been implicated in the pathogenesis of various diseases, including autoimmune disorders. Klotho has been shown to influence autophagy in different tissues and conditions (Li et al., 2022). Restoration of normal autophagy activity by Klotho has been observed in neurodegenerative diseases and kidney diseases, suggesting its protective role (Li et al., 2022). In the context of vascular calcification, Klotho deficiency has been associated with increased autophagy and vascular calcification, while supplementation of Klotho enhances autophagy and ameliorates vascular calcification (Li et al., 2022).


Klotho and Inflammation:


Inflammation plays a crucial role in the pathogenesis of autoimmune disorders. Klotho has been found to possess anti-inflammatory properties, making it a potential therapeutic agent for inflammatory conditions, including diabetic nephropathy (Typiak & Piwkowska, 2021). Klotho's anti-inflammatory actions have been attributed to its ability to modulate cellular senescence and inflammation pathways (Typiak & Piwkowska, 2021). The use of Klotho in diagnostics and immunotherapy of diabetes and diabetic nephropathy has been proposed (Typiak & Piwkowska, 2021).


The emerging evidence suggests that Klotho plays a significant role in autoimmune disorders. Its neuroprotective, anti-inflammatory, and autophagy-modulating properties make it an attractive target for therapeutic interventions in autoimmune diseases. Further research is needed to elucidate the precise mechanisms underlying the involvement of Klotho in autoimmune disorders and to explore its potential as a therapeutic agent.


Klotho & Respiratory Health


Klotho, an anti-aging protein, has been implicated in various aspects of respiratory health. Several studies have explored the relationship between Klotho and respiratory conditions such as chronic obstructive pulmonary disease (COPD), lung cancer, interstitial lung abnormalities (ILA), and lymphangioleiomyomatosis (LAM) (Pako et al., 2017; Avin et al., 2014; Chen et al., 2010; Takegahara et al., 2021; Buendía-Roldán et al., 2019; Feger et al., 2013).


In patients with COPD, the accelerated aging of the lung is a characteristic feature. A study by Pako et al. (2017) investigated the plasma concentration of Klotho in COPD patients undergoing pulmonary rehabilitation. The researchers found that the clinical condition of COPD patients was reflected in plasma Klotho concentration. This suggests that Klotho may be involved in the pathomechanism of chronic respiratory diseases.


Exercise has been shown to have beneficial effects on respiratory health. Avin et al. (2014) explored the role of Klotho in skeletal muscle as a regulator of longevity. The study suggested that exercise-induced increases in Klotho may be a response to increased intramuscular fat oxidation, which helps maintain tissue lipid supplies under conditions of increased utilization. This finding highlights the potential role of Klotho in maintaining physiological energy balance and its relevance to respiratory health.


In lung cancer, Klotho has been found to function as a tumor suppressor. Chen et al. (2010) demonstrated that the secreted Klotho protein can inhibit the activation of insulin/insulin-like growth factor 1 (IGF-1) receptors, suggesting that Klotho may function as a suppressor of lung cancer. Additionally, Takegahara et al. (2021) reported that Klotho inhibits epithelial-mesenchymal transition and increases sensitivity to pemetrexed, a chemotherapy drug, in lung adenocarcinoma cells. These findings highlight the potential therapeutic implications of Klotho in lung cancer treatment.


In individuals with ILA, lower levels of α-Klotho in serum were associated with decreased lung function. Buendía-Roldán et al. (2019) found that ILA subjects had lower lung diffusing capacity and higher concentrations of serum matrix metalloprotease-7 compared to controls. This suggests that α-Klotho may play a role in the progression of ILA and the decline of pulmonary function.


Furthermore, Feger et al. (2013) discussed the interplay between Klotho and FGF23 in various disorders, including respiratory diseases. Reduced levels of 1,25(OH)2D3, which is associated with respiratory infections and cardiovascular disease, are inhibited by the joint action of Klotho and FGF23. This highlights the potential involvement of Klotho in maintaining phosphate homeostasis and its implications in respiratory health.


In summary, Klotho has been implicated in various aspects of respiratory health, including COPD, lung cancer, ILA, and LAM. It may play a role in the pathomechanism of chronic respiratory diseases, maintain physiological energy balance, suppress lung cancer growth, and contribute to the decline of pulmonary function. Further research is needed to fully understand the mechanisms underlying the relationship between Klotho and respiratory health.


Klotho & Ion Channels


Klotho, a protein with both membrane-bound and secreted forms, has been found to play a role in the regulation of ion channels (Huang, 2010). The secreted form of Klotho has been shown to affect the function of several important signaling pathways, including insulin-like growth factor, fibroblast growth factor, Wnt, and transforming growth factor β (Abolghasemi et al., 2019). These pathways are involved in various cellular processes, including cell growth, differentiation, and survival. By modulating these pathways, Klotho can impact the biogenesis of cancer (Abolghasemi et al., 2019).


In terms of ion channels, Klotho has been found to regulate the activity of several channels, including TRPV5 and TRPV6, which are involved in calcium reabsorption in the kidney (Huang, 2010). Klotho modifies the N-glycans of these channels, potentially through the hydrolysis of glucuronic acids, leading to changes in their function (Huang, 2010). Additionally, Klotho has been shown to regulate the renal potassium channel ROMK1, which is important for potassium secretion (Cha et al., 2009). Klotho's involvement in ion channel regulation extends beyond the kidney, as it has also been found to affect the voltage-gated K+ channel Kv1.3, which plays a role in the immune response (Almilaji et al., 2014).


Furthermore, Klotho has been implicated in the regulation of renal calcium homeostasis and renal potassium channel ROMK1, suggesting a broader function in ion channel regulation (Hu et al., 2013). It has also been shown to participate in the regulation of mineral ion metabolism by affecting the functionality of ion channels and co-transporter proteins in the kidney (Ohnishi et al., 2009). The in vivo importance of Klotho in the regulation of mineral ion metabolism is evident in Klotho knockout mice, which exhibit severely impaired mineral ion homeostasis (Ohnishi et al., 2009).


In addition to its role in ion channel regulation, Klotho has been found to have protective effects against oxidative stress (Kuro-o, 2008). It participates in the mechanism of protection against oxidative stress and acts on the vascular endothelium by inducing the production of nitric oxide (Pacheco & Goncalves, 2014). These protective effects may contribute to Klotho's role in aging and longevity (Sopjani et al., 2015).


Overall, Klotho plays a multifaceted role in the regulation of ion channels, impacting various signaling pathways and cellular processes. Its involvement in ion channel regulation extends beyond the kidney and includes channels involved in calcium reabsorption, potassium secretion, and immune response. Additionally, Klotho has protective effects against oxidative stress and may contribute to aging and longevity. Further research is needed to fully understand the mechanisms underlying Klotho's regulation of ion channels and its broader physiological implications.


Klotho & Infectious Diseases


Infectious diseases pose a significant threat to public health, particularly in vulnerable populations such as the elderly. The aging process is associated with a decline in immune function, making older individuals more susceptible to infections (Satoh et al., 2020). One factor that has been implicated in the immune response to infections is the Klotho protein. Klotho is a circulating anti-aging hormone that has been shown to have anti-inflammatory and anti-oxidative properties (Corcillo et al., 2020).


Recent studies have suggested that Klotho may play a role in the immune response to infections. In a study by , a mouse model of Acinetobacter baumannii infection was used to evaluate the immune responses in Klotho knockout mice (Satoh et al., 2020). The study found that aged mice lacking Klotho had higher mortality rates, increased bacterial burdens, and more severe lung injury compared to control mice. This suggests that Klotho may play a protective role in the immune response to bacterial infections.


Another study by explored the role of Fibroblast Growth Factor-23 (FGF-23), which activates FGFR/α-Klotho binary complexes, in innate immune responses (Fitzpatrick et al., 2018). Excess FGF-23 has been associated with inflammation and adverse infectious outcomes, particularly in patients with chronic kidney disease. This suggests that the interaction between FGF-23 and Klotho may have implications for the immune response to infections.


Overall, these studies suggest that Klotho may play a role in the immune response to infectious diseases, particularly in the aging population. Further research is needed to fully understand the mechanisms underlying the relationship between Klotho and infectious diseases and to explore potential therapeutic interventions targeting Klotho to enhance immune function in vulnerable populations.


Glycosaminoglycans & Infectious Disease


Glycosaminoglycans (GAGs) play a significant role in infectious diseases by mediating the interactions between pathogens and host cells (Kamhi et al., 2013). GAGs are complex carbohydrates that are ubiquitously present on the cell surface and in the extracellular matrix (Kamhi et al., 2013). These carbohydrates have structural diversity and complexity, allowing them to control a wide array of biological interactions that influence physiological and pathological processes (Kamhi et al., 2013). The interactions between GAGs and pathogens are crucial for the invasive potential of the pathogens (Kamhi et al., 2013).


One example of the role of GAGs in infectious diseases is the adhesion of circulating microbes to vascular surfaces in the presence of shear forces in flowing blood (Moriarty et al., 2012). In the case of Lyme disease, the Lyme spirochete mediates vascular adhesion through sequential interactions with host macromolecules, including fibronectin and GAGs (Moriarty et al., 2012). The binding of the pathogen to GAGs and fibronectin facilitates vascular adhesion and promotes pathogenesis (Moriarty et al., 2012).


GAGs have also been shown to bind to a wide variety of microbial pathogens, including viruses, bacteria, parasites, and fungi (Jinno & Park, 2014). These interactions between GAGs and pathogens are thought to promote pathogenesis by facilitating pathogen attachment, invasion, or evasion of host defense mechanisms (Jinno & Park, 2014). However, the role of GAGs in infectious diseases has not been extensively studied in vivo, and therefore, their pathophysiological significance and functions are largely unknown (Jinno & Park, 2014).


In the context of viral zoonotic diseases, the interactions between GAGs and zoonotic pathogens correspond to the first contact that results in the infection of host cells (Bauer et al., 2021). Recent research has shed light on the roles of GAGs in the pathogenesis of zoonotic diseases, providing potential therapeutic avenues for using GAGs in the treatment of these diseases (Bauer et al., 2021).


Furthermore, GAGs have been implicated in the infectious entry of certain viruses. For example, Merkel cell polyomavirus (MCV) requires engagement of non-sialylated GAG receptors for attachment to the cell surface and sialylated co-receptor glycans for post-attachment steps in the infectious entry process (Geoghegan et al., 2017). Similarly, many polyomaviruses, including JCV, BKV, SV40, and MCV, require sialylated glycans for infectious entry into cells (Geoghegan et al., 2017).


Overall, GAGs play a crucial role in infectious diseases by mediating the interactions between pathogens and host cells. These interactions are essential for pathogen attachment, invasion, and evasion of host defense mechanisms. Further research is needed to fully understand the pathophysiological significance and functions of GAGs in infectious diseases.


Klotho & Glycosaminoglycans


Klotho and glycosaminoglycans (GAGs) play important roles in various physiological processes. Klotho is a glycoprotein that acts as a cofactor for fibroblast growth factors (FGFs) and is involved in the regulation of phosphate and calcium metabolism (Hu et al., 2010). It has been shown that Klotho modifies glycans in the renal proximal tubule, leading to decreased transporter activity and proteolytic degradation of sodium-phosphate cotransporter proteins (Hu et al., 2010). Additionally, Klotho deficiency has been linked to vascular calcification in chronic kidney disease (CKD) (Hu et al., 2011). Klotho deficiency contributes to soft-tissue calcification by enhancing phosphaturia, preserving glomerular filtration, and directly inhibiting phosphate uptake by vascular smooth muscle (Hu et al., 2011).


Glycosaminoglycans, such as heparin and heparan sulfate, have been found to interact with FGFs and modulate their signaling activity (Kurosu et al., 2006). In the absence of Klotho, FGF23 requires exogenous heparin or glycosaminoglycan as a cofactor to stimulate FGF signaling (Kurosu et al., 2006). This suggests that glycosaminoglycans play a critical role in the biological activity of FGF23. Furthermore, it has been proposed that Klotho regulates FGF-23 signaling through interacting with glycosaminoglycans (Lanske, 2007). Experimental validation is needed to confirm this notion (Lanske, 2007).


Klotho deficiency has been implicated in various pathological conditions, including premature aging, uremic cardiomyopathy, and defective endothelial function (Lanske, 2007; Neyra & Hu, 2017). Klotho protein protects vascular endothelium by inhibiting endothelial inflammation (Neyra & Hu, 2017). Soluble Klotho protein has been suggested as a potential therapeutic agent for CKD patients (Neyra & Hu, 2017). Klotho deficiency also affects lipid metabolism and hypertension (Huang et al., 2017). FGF21, an endocrine hormone, requires β-Klotho as a co-receptor for binding and activation of FGFRs (Kurosu et al., 2007). The weak heparin-binding ability of FGF23 reduces its affinity for FGF receptors, and α-Klotho is necessary for FGF23's interaction with and activation of FGF receptors (Kovesdy & Quarles, 2013).


In summary, Klotho and glycosaminoglycans play important roles in various physiological processes, including phosphate and calcium metabolism, vascular calcification, lipid metabolism, and hypertension. Klotho acts as a cofactor for FGFs and interacts with glycosaminoglycans to modulate FGF signaling. Further research is needed to fully understand the mechanisms underlying the interactions between Klotho, glycosaminoglycans, and FGFs.


Klotho & Detoxification


Klotho, a longevity gene, has been found to play a role in detoxification processes in various contexts. One study suggests that Klotho is involved in the metabolism of reactive oxygen species (ROS), which are implicated in neurodegenerative disorders (Zimmermann et al., 2021). The complex of Klotho and FGF23 leads to the upregulation of detoxification enzymes, such as SOD2 and CAT, through the FOXO3a pathway, resulting in the detoxification of ROS (Zimmermann et al., 2021). Another study highlights the role of Klotho in coordinating bile acid detoxification enzymes in the liver, which is important for maintaining liver health (Ciaula et al., 2020). Additionally, Klotho has been shown to contribute to oxidative stress resistance and the prevention of oxidative DNA damage, further supporting its role in detoxification processes (Lanzani et al., 2020).


Furthermore, Klotho deficiency has been associated with a loss of protective mechanisms against oxidative stress and inflammation, which can predispose individuals to cardiovascular events (Lanzani et al., 2020). This suggests that Klotho may also play a role in detoxification processes related to cardiovascular health. In the context of acute kidney injury, αKlotho deficiency has been shown to contribute to lung damage by reducing endogenous antioxidative capacity and increasing oxidative damage (Ravikumar et al., 2016). Conversely, αKlotho replacement has been found to partially reverse these abnormalities and mitigate pulmonary complications (Ravikumar et al., 2016).


Overall, these studies suggest that Klotho is involved in detoxification processes through its regulation of ROS metabolism, coordination of detoxification enzymes, and contribution to oxidative stress resistance. Understanding the role of Klotho in detoxification may have implications for the development of therapeutic interventions for neurodegenerative disorders, liver health, cardiovascular disease, and acute kidney injury.


The Role of Klotho in Injuries Associated with Biological Agents


Injuries that occur from pharmaceutical biological agents are a topic of concern in public health, and understanding the underlying mechanisms is crucial for developing preventive and therapeutic strategies. Klotho, a transmembrane protein primarily expressed in the kidneys, has been implicated in various physiological processes, including aging, kidney function, and protection against injury (Hu et al., 2010).


Klotho and Renal Ischemia-Reperfusion Injury:


Studies have shown that Klotho deficiency is an early biomarker of renal ischemia-reperfusion injury (IRI) and that its replacement can be protective (Hu et al., 2010). Klotho upregulates neutrophil gelatinase-associated lipocalin (NGAL), which has a protective role in ischemic kidney injury (Hu et al., 2010). This suggests that Klotho may play a renoprotective role in injuries that occur from pharmaceutical biological agents involving renal complications.


Klotho and Apoptosis Regulation:


Klotho has been found to suppress apoptosis in various cell types, including alveolar epithelial cells and cardiomyocytes (Hu et al., 2021). In an oxidative damage model, Klotho attenuated oxidant-induced alveolar epithelial cell apoptosis and mitochondrial DNA damage (Hu et al., 2021). Additionally, Klotho suppressed ROS-induced apoptosis to improve cardiac function (Hu et al., 2021). These findings suggest that Klotho may have a protective effect against induced injuries that occur from pharmaceutical biological agents associated with apoptosis in relevant cell types.


Klotho and Inflammatory Cytokines:


Inflammatory cytokines, such as TWEAK and TNFα, have been shown to reduce renal Klotho expression through NFκB signaling (Moreno et al., 2011). However, Klotho overexpression has been associated with a beneficial effect on progressive renal injury and acute kidney injury (AKI) (Moreno et al., 2011). These findings suggest that Klotho may counteract the detrimental effects of induced inflammatory cytokines from pharmaceutical biological agents.


Klotho and Cardioprotection:


Klotho has been implicated in cardioprotection during ischemia/reperfusion (I/R) injury (Olejnik et al., 2020). Recombinant Klotho has been shown to reduce apoptosis in experimental ischemic acute kidney injury and renal and cerebral I/R injury (Olejnik et al., 2020). These findings suggest that Klotho may have a potential therapeutic role in pharmaceutical biological agent induced cardiac injuries.


Klotho and Diabetic Nephropathy:


Glomerular endothelial cell injury is a key factor in the development and progression of diabetic nephropathy (DN) (Wang et al., 2019). Klotho has been found to attenuate DN in mice and ameliorate high glucose-induced injury in human renal glomerular endothelial cells (Wang et al., 2019). This suggests that Klotho may have a protective effect against pharmaceutical biological agent induced renal injuries, including DN.


The available literature suggests that Klotho may play a significant role in protecting against various types of injuries, including those that may occur as a result of various pharmaceutical biological agents. Klotho has been implicated in renoprotection, apoptosis regulation, modulation of inflammatory cytokines, cardioprotection, and attenuation of diabetic nephropathy. Further research is needed to elucidate the specific mechanisms by which Klotho exerts its protective effects in various pharmaceutical biological agent injuries. Understanding the role of Klotho in various pharmaceutical biological agent injuries may provide insights into potential therapeutic strategies for preventing or mitigating adverse events.


In summary, Core Manna was, in part, developed to help assist the body with the upregulation of Klotho by supplying the body with several key compounds found in nature. By targeting Klotho, we may help spin The Golden Thread of Life and enhance our Immune/Inflammatory response systems through Glycoimmunology.





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