Klotho Molecular Pathways

[⬆︎][ AMPK ][⬆︎]

Adenosine Monophosphate-Activated Protein Kinase (AMPK)

This pathway potentially up regulates Klotho

Klotho Up-Regulates this Pathway

•(1)•

• Impact on Aging:

The 5' Adenosine Monophosphate-activated Protein Kinase (AMPK) is a critical energy-sensing enzyme that modulates cellular energy homeostasis. As cells age, energy balance is disrupted, leading to a decline in cellular functions and increased vulnerability to stress. Activation of AMPK promotes catabolic processes (like fatty acid oxidation and autophagy) while inhibiting anabolic processes (like lipid and protein synthesis). By doing so, AMPK promotes cellular health, reduces oxidative stress, and enhances longevity.

Interaction with Klotho can further enhance AMPK activation. Klotho is known to up-regulate AMPK activity, and this synergy can potentiate anti-aging effects by improving mitochondrial function, promoting autophagy, and reducing cellular stress.

•• Pathway <•> Klotho:

This Pathway Up-Regulates Klotho. Activation of AMPK has been associated with increased Klotho expression. Enhanced Klotho levels, in turn, can further support the cellular energy balance and longevity-promoting functions of AMPK.

••• Klotho <•> Pathway:

Klotho Up-Regulates AMPK. Klotho increases AMPK activation, either directly or indirectly, by improving cellular energy status. This further potentiates the benefits of AMPK in counteracting age-associated changes.

•••• Downstream Pathways:

Activation of AMPK affects several downstream pathways:

1. mTOR inhibition: AMPK activation inhibits mTOR, a major cellular growth pathway, thereby promoting autophagy and cellular cleanup.

2. PGC-1α activation: Enhancing mitochondrial biogenesis and function.

3. FOXO pathways: Involved in stress resistance, metabolism, and longevity.

4. Inhibition of inflammatory pathways like NF-κB.

••••• Reciprocal Response:

AMPK can Up-Regulate Klotho. A positive feedback loop exists wherein activation of AMPK increases Klotho expression, which in turn can further potentiate AMPK activation, amplifying the beneficial effects on cellular health and aging.

•••••• Diseases Associated with this Pathway:

1. Metabolic Disorders: Conditions like type 2 diabetes can be ameliorated by AMPK activation, and Klotho can enhance this effect.

2. Neurodegenerative Diseases: AMPK activation can be neuroprotective, and its interaction with Klotho might bolster these effects.

3. Cancers: AMPK inhibits mTOR and supports cellular energy balance, potentially reducing cancer risk. The interaction with Klotho could further modulate tumor dynamics.

4. Cardiovascular Diseases: Both AMPK and Klotho support cardiovascular health by reducing oxidative stress and improving vascular function.

••••••• Active Interventional Agents

1. Amino Acids: L-arginine and L-carnitine can modulate AMPK activation.

2. Nutritional Supplements: Resveratrol and Coenzyme Q10 have been found to activate AMPK.

3. Plant Derived Compounds: Berberine and Quercetin are known to up-regulate AMPK activity.

4. Hormones: Adiponectin, an adipose-derived hormone, activates AMPK.

5. Drugs: Metformin, a commonly prescribed anti-diabetic drug, is a known AMPK activator.

6. Peptides: AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) is a peptide that activates AMPK.

References:

[2023] The Anti-Aging Hormone Klotho Promotes Retinal Pigment Epithelium Cell Viability and Metabolism by Activating the AMPK/PGC-1α Pathway

We conclude that Klotho acts upstream of the AMPK/PGC-1α pathway and regulates RPE/retinal resistance to oxidative stress, mitochondrial function, and gene and protein expressions. Thus, KL decline during aging could negatively impact retinal health, inducing age-related retinal degeneration.

[⬆︎][ ACE2 ][⬆︎]

Angiotensin-Converting Enzyme 2 (ACE2)

This pathway Up-regulates Klotho

Klotho Up-Regulates this Pathway

•(2)•

• Impact on Aging:

The Angiotensin-Converting Enzyme 2 (ACE2) plays a significant role in the renin-angiotensin system (RAS). ACE2 balances the actions of Angiotensin II by converting it to Ang(1-7), a vasodilator. Aging is associated with a reduction in ACE2 levels, leading to the imbalance in RAS and thereby promoting inflammation, oxidative stress, fibrosis, and apoptosis which collectively contribute to aging-related pathological changes in multiple organs.

The interaction of Klotho with ACE2 helps in attenuating the adverse effects associated with Angiotensin II. Klotho enhances the expression of ACE2 and promotes the beneficial effects of Ang(1-7), thereby ameliorating the negative effects of aging.

•• Pathway <•> Klotho:

This Pathway Up-Regulates Klotho. ACE2, by reducing the adverse effects of Angiotensin II, creates an environment conducive to the expression and action of Klotho. Enhanced Klotho can counteract oxidative stress and inflammation, further supporting healthy aging.

••• Klotho <•> Pathway:

Klotho Up-Regulates ACE2. When Klotho is enhanced, it promotes the expression of ACE2, which subsequently helps in the conversion of Angiotensin II to Ang(1-7). This interaction has implications for countering aging-related diseases, especially cardiovascular diseases.

•••• Downstream Pathways:

The activation of ACE2 leads to the production of Ang(1-7), which binds to its receptor, Mas. The Ang(1-7)/Mas axis then promotes vasodilation, anti-inflammatory actions, and anti-fibrotic activities. Moreover, the ACE2/Ang(1-7)/Mas pathway inhibits the MAPK signaling pathway, NF-kB pathway, and reduces oxidative stress, which are all essential mechanisms for promoting cellular health and longevity.

••••• Reciprocal Response:

ACE2 can Up-Regulate Klotho. When ACE2 is directly activated, it can promote a favorable environment for Klotho expression, forming a reciprocal regulatory feedback loop where each enhances the other, promoting better aging outcomes.

•••••• Diseases Associated with this Pathway:

1. Cardiovascular Diseases: Enhanced ACE2/Klotho interaction reduces the risk of hypertension and atherosclerosis.

2. Kidney Diseases: The ACE2/Klotho axis plays a protective role against kidney fibrosis and chronic kidney disease.

3. Lung Diseases: Reduced ACE2 levels can lead to increased susceptibility to acute respiratory diseases, and Klotho can counteract these adverse effects.

4. Neurological Diseases: Imbalance in ACE2 can contribute to neurological conditions like Alzheimer's, and the interaction with Klotho might provide neuroprotective effects.

••••••• Active Interventional Agents:

1. Amino Acids: L-Arginine can stimulate the expression of ACE2.

2. Peptides: Ang(1-7) directly acts on the ACE2 pathway.

3. Drugs: ACE inhibitors and Angiotensin Receptor Blockers (ARBs) indirectly modulate ACE2 activity.

4. Nutritional Supplements: Resveratrol has been shown to increase ACE2 expression.

5. Plant Derived Compounds: Epigallocatechin gallate (EGCG) from green tea can elevate ACE2 levels.

6. Hormones: Estrogen can modulate ACE2 expression and activity.

References:

[2022] Klotho restoration via ACE2 activation- A potential therapeutic strategy against acute kidney injury-diabetes comorbidity.pdf

These findings indicate that IRI leads to the development of AKI, in which hyperglycemia is a risk factor. Remarkably, DIZE treatment resulted in a significant decrease in BUN, plasma creatinine, and urinary KIM-1 levels and restoration of renal ACE2, systemic Ang-(1-7), and Klotho levels, suggesting that ACE2 activation may play an important role in Klotho regulation and thus renoprotection in AKI.

[⬆︎][ cAMP ][⬆︎]

Cyclic Adenosine Monophosphate pathway (cAMP)

This pathway potentially down regulates Klotho

Klotho Up-Regulates this Pathway

•(3)•

• Impact on Aging:

Cyclic Adenosine Monophosphate (cAMP) is a second messenger that plays a pivotal role in numerous cellular processes, including energy metabolism, cell proliferation, and differentiation. It mediates its effects primarily via Protein Kinase A (PKA). As aging progresses, there's a decline in cAMP levels in various tissues, which might contribute to reduced cellular responsiveness, energy imbalance, and diminished cellular function.

The interaction of Klotho with the cAMP pathway can further enhance the cellular responsiveness and counter some of the age-associated cellular dysfunctions. Klotho has been shown to influence cAMP levels, potentially potentiating its signaling and thereby exerting anti-aging effects.

•• Pathway <•> Klotho:

This Pathway Up-Regulates Klotho. Elevation in cAMP levels has been associated with an increase in Klotho expression. This enhanced Klotho expression can further potentiate cAMP's cellular responses, optimizing cellular function in the context of aging.

••• Klotho <•> Pathway:

Klotho Up-Regulates cAMP. Klotho can influence the production of cAMP, augmenting its levels and enhancing downstream signaling pathways associated with cellular health, energy balance, and longevity.

•••• Downstream Pathways:

cAMP-mediated effects are primarily executed through its activation of:

1. PKA: Activating numerous cellular functions from metabolism to transcription.

2. Exchange protein directly activated by cAMP (EPAC): Mediating cellular processes like calcium signaling and gene transcription.

3. Cyclic nucleotide-gated ion channels: Influencing neuronal and sensory processes.

••••• Reciprocal Response:

cAMP can Up-Regulate Klotho. There seems to be a positive feedback loop where an increase in cAMP levels boosts Klotho expression, which in turn can potentiate cAMP production and signaling, supporting cellular health and counteracting aging effects.

•••••• Diseases Associated with this Pathway:

1. Metabolic Disorders: Reduced cAMP signaling can impact glucose homeostasis, and its interaction with Klotho can modulate these effects.

2. Neurodegenerative Diseases: cAMP/PKA signaling plays a role in synaptic function and memory. Klotho interaction might influence cognitive outcomes.

3. Cardiovascular Diseases: cAMP affects heart contractility and vascular function. Its interaction with Klotho might affect cardiovascular health.

4. Immune Disorders: cAMP modulates immune cell function, and its dynamics with Klotho could impact immune responses.

••••••• Active Interventional Agents

1. Amino Acids: Caffeine can elevate cAMP levels by inhibiting phosphodiesterases.

2. Nutritional Supplements: Forskolin, derived from the Coleus plant, stimulates cAMP production.

3. Plant Derived Compounds: Epinephrine and norepinephrine, through their action on adrenergic receptors, can increase cAMP levels.

4. Hormones: Glucagon and Parathyroid hormone (PTH) act through G-protein coupled receptors to elevate cAMP levels.

5. Drugs: Beta-adrenergic agonists and Phosphodiesterase inhibitors can elevate cAMP levels.

References:

[2023] Neuroprotective Role of Klotho on Dementia

Many biological activities of Klotho have been found; however, their molecular processes are unknown and must be explained. Research has shown that circulating Klotho has a role in intracellular signaling cascades by modulating the activity of multiple cell surface receptors, including TGF-β1 [18,19], p53/p21 [30], cyclic adenosine monophosphate (c-AMP) [31], protein kinase C (PKC) [32], Wnt signaling pathways [33], FGF-23 signaling [34], and insulin/IGF-1 [35]. Each signaling pathway that involves Klotho is described below in more detail.

[⬆︎][ eNOS/NO ][⬆︎]

Molecular Pathway: endothelial Nitric Oxide Synthase (eNOS)

This pathway Up-Regulates Klotho

Klotho Up-Regulates this Pathway

•(4)•

• Impact on Aging:

Endothelial Nitric Oxide Synthase (eNOS) is an enzyme responsible for producing nitric oxide (NO) in endothelial cells. NO plays a crucial role in vascular health by promoting vasodilation, reducing platelet aggregation, and inhibiting leukocyte adhesion to the endothelium. As aging progresses, there can be a decline in eNOS activity and a corresponding decrease in NO production. This reduction can contribute to endothelial dysfunction, a precursor to atherosclerosis, and other age-related vascular diseases.

The interaction of Klotho with the eNOS pathway has been studied. Klotho appears to enhance the bioavailability of NO, potentially by upregulating eNOS expression and activity, thus counteracting age-associated vascular dysfunction.

•• Pathway <•> Klotho:

This Pathway Up-Regulates Klotho. Activation of eNOS and increased NO production have been associated with elevated Klotho levels. The protective effects of NO, especially in the vascular system, might synergize with Klotho's anti-aging properties.

••• Klotho <•> Pathway:

Klotho Up-Regulates eNOS. Klotho can enhance eNOS expression and its enzymatic activity, leading to increased NO production. This effect reinforces the protective and vasodilatory actions of NO in the vasculature.

•••• Downstream Pathways:

eNOS-mediated NO production influences various pathways:

1. cGMP Pathway: NO activates guanylate cyclase, increasing cyclic guanosine monophosphate (cGMP) levels, leading to vasodilation.

2. Inhibition of Platelet Aggregation: NO prevents platelets from adhering and aggregating, reducing thrombus formation.

3. Modulation of Inflammation: NO inhibits the adhesion of white blood cells to endothelial cells, reducing vascular inflammation.

4. Mitochondrial Respiration: NO modulates the electron transport chain, affecting cellular energy dynamics.

••••• Reciprocal Response:

eNOS can Up-Regulate Klotho. The enhanced bioavailability of NO, through eNOS activation, might upregulate Klotho expression, creating a positive feedback loop that promotes vascular health and counteracts aging-associated vascular changes.

•••••• Diseases Associated with this Pathway:

1. Atherosclerosis: Reduced eNOS activity and NO production can lead to endothelial dysfunction, a precursor to atherosclerosis.

2. Hypertension: Diminished NO bioavailability can result in vasoconstriction and elevated blood pressure.

3. Ischemic Heart Diseases: Impaired eNOS function can affect coronary blood flow and oxygen supply.

4. Erectile Dysfunction: eNOS is essential for penile blood flow and erection.

   ⫸ Observational Indication of increased Klotho levels

The interaction of Klotho with eNOS in these diseases could have therapeutic implications, potentially modulating disease severity or progression.

••••••• Active Interventional Agents:

1. Amino Acids: L-arginine serves as a substrate for eNOS to produce NO.

2. Nutritional Supplements: Folic acid can enhance eNOS activity.

3. Plant Derived Compounds: Resveratrol, found in grapes, has been shown to upregulate eNOS expression.

4. Drugs: Statins, commonly used cholesterol-lowering agents, like Lipitor, can increase eNOS expression. Phosphodiesterase-5 inhibitors, like sildenafil, increase NO effects in tissues.

5. Hormones: Estrogen can modulate eNOS activity and NO production.

References:

[2017] α-Klotho expression determines nitric oxide synthesis in response to FGF-23 in human aortic endothelial cells

FGF-23 increases cell proliferation, NO production, eNOS protein expression, and eNOS activation in human aortic but not brain microvascular endothelial cells, in vitro

[⬇︎][ Epigenetic ][⬆︎]

Molecular Pathway: Epigenetic Modification Pathway

This pathway down regulates Klotho

Klotho Up-Regulates this Pathway

•(5)•

• Impact on Aging:

Epigenetics refers to modifications in gene expression without changes to the underlying DNA sequence. These modifications include DNA methylation, histone modification, and non-coding RNA-associated gene silencing. Epigenetic changes accumulate over a lifetime and can influence aging by affecting gene expression patterns, cellular function, and the ability of cells to respond to environmental cues. These changes can lead to age-related diseases, cellular senescence, and ultimately affect lifespan.

Klotho has been shown to interact with the epigenetic machinery. For instance, Klotho expression itself can be regulated epigenetically, and changes in its expression might have downstream effects on aging processes via epigenetic modulation.

•• Pathway <•> Klotho:

This Pathway Modifies Klotho. Epigenetic modifications, such as DNA methylation at the Klotho gene locus or histone modifications surrounding it, can influence the expression of Klotho. This means that epigenetic changes that occur during aging reduce Klotho expression, potentially accelerating aging processes.

••• Klotho <•> Pathway:

Klotho Modifies the Epigenetic Pathway. Klotho can influence epigenetic enzymes, such as those involved in DNA methylation and histone modification. By modulating these enzymes, Klotho can potentially affect the epigenetic landscape of cells, influencing gene expression patterns related to aging and longevity.

•••• Downstream Pathways:

Epigenetic modifications can influence various downstream pathways:

1. DNA Repair: Epigenetics can regulate the expression of genes involved in DNA repair mechanisms.

2. Cell Cycle Regulation: Epigenetic modifications can influence genes that control cell proliferation and senescence.

3. Metabolic Pathways: Epigenetics modulates genes that govern cellular metabolism.

4. Inflammatory and Stress Response Pathways: Epigenetic changes can upregulate or downregulate genes involved in inflammation and cellular stress responses.

••••• Reciprocal Response:

Epigenetic changes can Modify Klotho expression. Epigenetic modifications, especially DNA methylation at the Klotho gene locus, can influence its expression. An age-related increase in methylation at this locus could lead to reduced Klotho levels, potentially influencing aging processes.

•••••• Diseases Associated with this Pathway:

1. Age-related Cognitive Decline: Epigenetic modifications can influence neuronal gene expression patterns and synaptic plasticity.

2. Cancers: Aberrant epigenetic landscapes can lead to deregulated gene expression, promoting tumorigenesis.

3. Cardiovascular Diseases: Epigenetic changes can influence vascular health and function.

4. Metabolic Disorders: Epigenetics plays a role in regulating metabolic gene expression.

5. Autoimmune Diseases: Epigenetic modifications can influence immune cell function and self-tolerance.

Klotho's interaction with the epigenetic machinery in these diseases can modulate disease progression or outcomes.

••••••• Active Interventional Agents

1. Amino Acids: S-Adenosyl methionine (SAM) serves as a methyl donor in DNA methylation processes.

2. Nutritional Supplements: Folic acid and vitamin B12 play roles in the one-carbon metabolism pathway that produces SAM.

3. Plant Derived Compounds: Genistein, found in soy, has been shown to influence DNA methylation.

4. Drugs: DNA methyltransferase inhibitors like 5-azacytidine, and histone deacetylase inhibitors like vorinostat, modulate the epigenetic landscape.

5. Non-coding RNAs: microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play roles in gene silencing and epigenetic regulation.

References:

[2023] New Insights into the Genetics and Epigenetics of Aging Plasticity

[2023] Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity

[2023] Upstream and downstream regulators of Klotho expression in chronic kidney disease

[⬆︎][ FGF19 ][⬆︎]

Fibroblast Growth Factor 19 pathway (FGF19)

This pathway potentially down regulates Klotho

Klotho Modulates this Pathway

•(6)•

• Impact on Aging:

Fibroblast Growth Factor 19 (FGF19) is a member of the FGF family, primarily involved in bile acid metabolism, glucose homeostasis, and lipid metabolism. Altered levels or activity of FGF19 have been implicated in various metabolic disorders. As metabolic dysfunction is a hallmark of aging, proper regulation and action of FGF19 could have implications for healthy aging and longevity.

Klotho, specifically its variant β-Klotho, acts as a co-receptor for FGF19 (as well as for FGF21). The interaction between Klotho and FGF19 is crucial for the latter's metabolic effects and signaling pathway activation.

•• Pathway <•> Klotho:

This Pathway Up-Regulates Klotho. FGF19 binding to its receptor complex, which includes β-Klotho, can enhance the expression and stabilization of Klotho proteins. This interaction underscores the importance of β-Klotho in mediating FGF19's metabolic effects.

••• Klotho <•> Pathway:

Klotho Modifies the FGF19 pathway. β-Klotho, a variant of the Klotho protein, is vital for FGF19 to bind to its receptor and initiate downstream signaling. Without adequate β-Klotho, FGF19 signaling would be inefficient, affecting its metabolic regulatory actions.

•••• Downstream Pathways:

Upon binding to its receptor complex, FGF19 initiates various downstream pathways:

1. Bile Acid Synthesis: FGF19 inhibits bile acid synthesis in the liver by downregulating CYP7A1, a key enzyme in this process.

2. Gluconeogenesis Regulation: FGF19 reduces hepatic gluconeogenesis, which helps in glucose homeostasis.

3. Lipid Metabolism: FGF19 influences lipid metabolism, specifically reducing triglyceride levels.

••••• Reciprocal Response:

FGF19 can Up-Regulate Klotho. Increased FGF19 levels, particularly in response to bile acid metabolism, can lead to upregulation of β-Klotho, facilitating more efficient FGF19 signaling.

•••••• Diseases Associated with this Pathway:

1. Metabolic Syndrome: Disruption in FGF19 signaling can be linked to metabolic dysregulation, including glucose intolerance and lipid abnormalities.

2. Cholestasis: Altered FGF19 levels can affect bile acid homeostasis, leading to cholestasis.

3. Non-Alcoholic Fatty Liver Disease (NAFLD): Imbalances in FGF19 levels and signaling can contribute to the progression of NAFLD.

4. Bile Acid Diarrhea: Insufficient FGF19 production can result in excessive bile acid synthesis, leading to diarrhea.

The interaction of Klotho (β-Klotho) with FGF19 in these diseases might offer therapeutic avenues for disease modulation.

••••••• Active Interventional Agents:

1. Amino Acids: Certain amino acids, upon metabolism, can influence bile acid synthesis and potentially FGF19 signaling.

2. Nutritional Supplements: Some agents, like cholic acid, might impact bile acid metabolism and FGF19 regulation.

3. Drugs: Obeticholic acid, an FXR agonist, affects bile acid homeostasis and could influence FGF19 levels.

4. Hormones: Insulin might have an indirect role in modulating FGF19 through its effects on glucose and lipid metabolism.

References:

[2023] Biological and pharmacological functions of the FGF19- and FGF21-coreceptor beta klotho

[⬆︎][ FGF21 ][⬆︎]

Fibroblast Growth Factor 21 Pathway (FGF21)

This pathway potentially Up-Regulates Klotho

Klotho Modulates this Pathway

•(7)•

• Impact on Aging:

Fibroblast Growth Factor 21 (FGF21) is a metabolic hormone predominantly produced in the liver. It plays vital roles in regulating glucose and lipid metabolism, energy homeostasis, and response to stress, especially nutritional stress like fasting. Aging is often associated with metabolic imbalances and increased susceptibility to stressors, and FGF21's actions are considered protective against various age-related metabolic disorders.

Klotho, in particular its variant β-Klotho, serves as a co-receptor for FGF21. This interaction is essential for the proper signaling and physiological effects of FGF21, which might be significant in the context of aging.

•• Pathway <•> Klotho:

This Pathway Up-Regulates Klotho. When FGF21 binds to its receptor complex, which includes β-Klotho, it can increase the stabilization and activity of Klotho proteins. This interaction emphasizes the role of β-Klotho in mediating FGF21's beneficial metabolic effects.

••• Klotho <•> Pathway:

Klotho Modifies the FGF21 pathway. β-Klotho, a form of the Klotho protein, is crucial for FGF21 to bind to its receptor and activate downstream signaling. A deficiency or alteration in β-Klotho would disrupt FGF21 signaling and its metabolic regulatory actions.

•••• Downstream Pathways:

Upon FGF21 signaling initiation:

1. Lipid Metabolism: FGF21 promotes lipid oxidation in the liver and reduces triglyceride content, thereby protecting against fatty liver disease.

2. Insulin Sensitivity: FGF21 enhances insulin sensitivity, beneficial for preventing insulin resistance and type 2 diabetes.

3. Energy Expenditure: FGF21 increases energy expenditure, aiding in weight regulation.

4. Stress Response: FGF21 helps in mitigating oxidative stress and offers protection against nutritional stressors.

••••• Reciprocal Response:

FGF21 can Up-Regulate Klotho. Enhanced FGF21 activity and levels, particularly in metabolic stress situations, can lead to the upregulation of β-Klotho, ensuring efficient FGF21 signaling.

•••••• Diseases Associated with this Pathway:

1. Metabolic Syndrome: Disrupted FGF21 signaling contributes to metabolic imbalances, like glucose intolerance and lipid disorders.

2. Non-Alcoholic Fatty Liver Disease (NAFLD): FGF21's role in lipid metabolism associates it with NAFLD progression and management.

3. Type 2 Diabetes: Altered FGF21 levels or signaling can be found in diabetic patients, affecting glucose homeostasis.

4. Obesity: Changes in FGF21 activity can influence body weight regulation and energy homeostasis.

The partnership between Klotho (specifically β-Klotho) and FGF21 in these conditions might provide potential therapeutic interventions or disease markers.

••••••• Active Interventional Agents:

1. Amino Acids: Certain amino acids can indirectly influence FGF21 through their metabolic pathways.

2. Nutritional Supplements: Agents impacting mitochondrial function or oxidative stress might modify FGF21 activity.

3. Plant Derived Compounds: Resveratrol, commonly found in grapes, can influence FGF21 expression and its downstream signaling.

4. Drugs: Thiazolidinediones, used in diabetes management, can alter FGF21 levels and its metabolic effects.

References:

[2023] Biological and pharmacological functions of the FGF19- and FGF21-coreceptor beta klotho

[⬆︎][ FGF23 ][⬆︎]

Fibroblast Growth Factor 23 (FGF23) Pathway

This pathway Up-Regulates Klotho

Klotho Up-Regulates this Pathway

•(8)•

• Impact on Aging:

Fibroblast Growth Factor 23 (FGF23) is primarily recognized as a hormone that regulates phosphate and vitamin D metabolism in the kidney. The balance of these minerals plays a pivotal role in bone mineralization, cardiovascular health, and overall metabolic health. As one ages, disturbances in phosphate, calcium, and vitamin D balance can lead to multiple health issues, including osteoporosis, arterial calcifications, and other age-related diseases.

The Klotho protein, especially the membrane-bound form, acts as a co-receptor, allowing FGF23 to bind to its receptors and mediate its effects. The interaction between Klotho and FGF23 is fundamental for maintaining mineral homeostasis, which is directly associated with the aging process.

•• Pathway <•> Klotho:

This Pathway Up-Regulates Klotho. The binding of FGF23 to its receptor complex requires Klotho. When FGF23 levels rise, it can increase the expression and stabilization of Klotho, ensuring effective signaling and proper phosphate and vitamin D regulation.

••• Klotho <•> Pathway:

Klotho Modifies the FGF23 pathway. The Klotho protein is essential for FGF23 signaling. Without adequate Klotho, FGF23 cannot effectively bind to its receptor, leading to disturbances in phosphate and vitamin D metabolism, which can accelerate aging-related conditions.

•••• Downstream Pathways:

FGF23 signaling majorly affects:

1. Phosphate Excretion: FGF23 promotes urinary phosphate excretion by reducing the expression of sodium-phosphate co-transporters in the kidney.

2. Vitamin D Metabolism: FGF23 suppresses the conversion of 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D, by downregulating the enzyme 1-alpha-hydroxylase in the kidney.

••••• Reciprocal Response:

There is a Reciprocal Response between FGF23 and Klotho. High phosphate levels or active vitamin D compounds can increase FGF23 production. In turn, the rise in FGF23 can upregulate Klotho, forming a feedback loop that ensures mineral homeostasis.

•••••• Diseases Associated with this Pathway:

1. Chronic Kidney Disease (CKD): Elevated FGF23 levels are often seen in CKD, contributing to renal osteodystrophy and cardiovascular complications.

2. Hyperphosphatemia: Elevated blood phosphate levels can lead to increased FGF23, disturbing mineral balance.

3. Familial Tumoral Calcinosis: Caused by mutations leading to loss of FGF23 function, resulting in hyperphosphatemia.

4. Osteoporosis: Imbalances in FGF23 can indirectly affect bone mineral density.

5. Cardiovascular Diseases: High FGF23 levels have been associated with left ventricular hypertrophy and arterial calcifications.

In these diseases, the relationship between Klotho and FGF23 may offer therapeutic targets or prognostic markers.

••••••• Active Interventional Agents:

1. Amino Acids & Peptides: Some might indirectly influence FGF23 through bone metabolism.

2. Vitamins: Vitamin D and its analogs can influence FGF23 production.

3. Minerals: Phosphate binders can modulate circulating FGF23 levels by reducing intestinal phosphate absorption.

4. Drugs: Cinacalcet, a calcimimetic, can affect parathyroid hormone (PTH) and consequently FGF23 levels.

References:

[2018] FGF23 Actions on Target Tissues—with and without Klotho

[2020] FGF23 contains two distinct high-affinity binding sites enabling bivalent interactions with α-Klotho

FGF Receptors (FGFRs): Klotho binds to various FGFRs to form a complex that can specifically bind to FGF23. This interaction is critical for phosphate and vitamin D homeostasis in the body. FGFR1c, FGFR3c, and FGFR4 have been found to bind to Klotho in various tissues.

[⬆︎][ Insulin ][⬆︎]

Insulin Signaling Pathway

This pathway does not Up-Regulate Klotho

Klotho does Up-Regulates this Pathway

•(9)•

• Impact on Aging:

Insulin is a peptide hormone produced by beta cells of the pancreatic islets. It plays a key role in regulating glucose homeostasis by promoting cellular uptake of glucose and its utilization or storage. Dysregulation in insulin signaling, such as insulin resistance, is associated with metabolic disorders like type 2 diabetes, which can accelerate cellular senescence and contribute to various aging-related diseases. Aging is also linked with reduced insulin sensitivity.

Klotho has been demonstrated to have a protective effect against insulin resistance. Thus, the interaction between insulin and Klotho is vital in modulating age-related metabolic dysfunction.

•• Pathway <•> Klotho:

This pathway Up-Regulates Klotho. Insulin can up-regulate the expression of Klotho. Increased Klotho levels can in turn enhance insulin sensitivity, suggesting a beneficial feedback mechanism.

••• Klotho <•> Pathway:

Klotho Up-Regulates the insulin pathway. Klotho enhances insulin sensitivity by suppressing intracellular pathways that hinder insulin signaling. It opposes the insulin antagonist, Wnt, thus promoting proper insulin action and glucose homeostasis.

•••• Downstream Pathways: Insulin signaling affects various cellular processes, including:

1. Glucose Uptake: By increasing the translocation of GLUT4 transporters to the cell membrane in muscle and adipose tissue.

2. Glycogen Synthesis: Stimulating glycogenesis in the liver.

3. Lipid Metabolism: Promoting lipid synthesis and inhibiting lipolysis.

4. Protein Synthesis: Activating the mTOR pathway, promoting cellular growth and protein synthesis.

••••• Reciprocal Response:

There is a Reciprocal Response between insulin and Klotho. The enhancement of insulin sensitivity by Klotho can reduce the compensatory hyperinsulinemia seen in insulin-resistant states. This reduces stress on pancreatic beta cells and potentially slows the progression to type 2 diabetes.

•••••• Diseases Associated with this Pathway:

1. Type 2 Diabetes: Due to insulin resistance and pancreatic beta-cell dysfunction.

2. Metabolic Syndrome: A cluster of conditions including hypertension, hyperglycemia, and central obesity.

3. Polycystic Ovary Syndrome (PCOS): Often associated with insulin resistance.

4. Cardiovascular Diseases: Insulin resistance is a risk factor for atherosclerosis and other heart diseases.

5. Non-alcoholic Fatty Liver Disease (NAFLD): Associated with insulin resistance.

Klotho's role in enhancing insulin sensitivity can be protective against these conditions.

••••••• Active Interventional Agents:

1. Amino Acids & Peptides: Exogenous insulin and insulin analogs.

2. Metals: Chromium is believed to enhance insulin action.

3. Plant-Derived Compounds: Berberine and bitter melon have been suggested to modulate insulin sensitivity.

4. Drugs: Metformin, sulfonylureas, thiazolidinediones, and GLP-1 receptor agonists are among many that affect insulin signaling or secretion.

[⬆︎][ ISP ][⬆︎]

Insulin Signaling Pathway (ISP)

This Pathway Up-regulates Klotho

Klotho Up-Regulates this Pathway

•(10)•

• Impact on Aging:

The Insulin Signaling Pathway (ISP) is central to glucose homeostasis, lipid metabolism, and overall energy balance. Alterations or dysfunctions in ISP are associated with a myriad of metabolic disorders, including type 2 diabetes, obesity, and cardiovascular diseases, all of which are related to the aging process. Aging often sees a decline in the efficiency of ISP, resulting in reduced cellular responsiveness to insulin, known as insulin resistance.

Klotho proteins have been proposed to be enhancers of insulin sensitivity, and alterations in Klotho expression may impact the functionality of the ISP, influencing aging and age-related diseases.

•• Pathway <•> Klotho:

This pathway Up-Regulates Klotho. Activation of the ISP may result in up-regulation of Klotho expression. Increased Klotho levels then enhance insulin sensitivity, suggesting a positive feedback loop that favors metabolic health.

••• Klotho <•> Pathway:

Klotho Up-Regulates the ISP. Klotho acts to enhance the efficacy of the ISP by improving insulin sensitivity. By opposing insulin antagonistic pathways, like the Wnt signaling pathway, Klotho fosters efficient insulin action and optimized glucose metabolism.

•••• Downstream Pathways:

ISP, upon insulin binding, initiates several cellular responses:

1. Glucose Uptake: Facilitated by translocation of GLUT4 transporters in muscle and adipose tissue.

2. Glycogen Synthesis: Enhanced glycogenesis in liver cells.

3. Lipid Metabolism: Promotion of lipid synthesis and inhibition of lipolysis.

4. mTOR Signaling: Impacting cellular growth, autophagy, and protein synthesis.

5. FOXO Transcription Factors: Regulation of genes involved in stress resistance, metabolism, and cellular longevity.

••••• Reciprocal Response:

There's a Reciprocal Response between ISP and Klotho. When ISP efficiency is enhanced due to improved insulin sensitivity (possibly via Klotho), there is reduced hyperinsulinemia. This minimizes undue stress on pancreatic beta cells, potentially slowing the progression of conditions like type 2 diabetes.

•••••• Diseases Associated with this Pathway:

1. Type 2 Diabetes: Rooted in insulin resistance and beta-cell dysfunction.

2. Metabolic Syndrome: Conditions like hypertension, hyperglycemia, and obesity co-exist.

3. Polycystic Ovary Syndrome (PCOS): Insulin resistance often present.

4. Cardiovascular Diseases: Linked to insulin resistance.

5. Non-alcoholic Fatty Liver Disease (NAFLD): Due to insulin resistance and altered lipid metabolism.

Klotho's potential to boost insulin sensitivity can be protective against these disorders.

••••••• Active Interventional Agents:

1. Peptides: Insulin and insulin analogs.

2. Metals: Chromium, suggested to enhance insulin action.

3. Plant-Derived Compounds: Berberine, fenugreek, and bitter melon can influence insulin sensitivity.

4. Drugs: Agents like metformin, sulfonylureas, thiazolidinediones, SGLT-2 inhibitors, and GLP-1 receptor agonists modulate ISP or insulin secretion.

[⬇︎][ IGF1 ][⬇︎]

Insulin-Like Growth Factor 1 Pathway (IGF-1 Pathway)

This pathway Down-Regulates Klotho

Klotho Down-Regulates this Pathway

•(11)•

• Impact on Aging:

The Insulin-Like Growth Factor 1 Pathway (IGF-1 Pathway) is involved in cell growth, differentiation, and metabolic regulation. Elevated levels of IGF-1 have been associated with increased growth and reduced apoptosis, while reduced IGF-1 signaling is linked to longevity in various organisms. Overactivity of the IGF-1 pathway might accelerate the aging process through promoting cellular proliferation and inhibiting cellular repair mechanisms.

Klotho has an inhibitory effect on the IGF-1 receptor, suggesting that Klotho may modulate the IGF-1 signaling pathway's impact on aging.

•• Pathway <•> Klotho:

The IGF-1 pathway Down-Regulates Klotho. Increased IGF-1 signaling can suppress the expression of Klotho. A reduction in Klotho may enhance the proliferative actions of IGF-1, which could be detrimental in the context of aging.

••• Klotho <•> Pathway:

Klotho Down-Regulates the IGF-1 pathway. Klotho can inhibit IGF-1 signaling by interacting with the IGF-1 receptor, thereby acting as a negative regulator. This inhibitory effect can be protective against excessive cellular proliferation and might promote cellular repair and longevity.

•••• Downstream Pathways:

IGF-1 signaling influences several cellular responses:

1. PI3K/Akt Pathway: Regulating cell survival, growth, and proliferation.

2. MAPK/ERK Pathway: Impacting cell differentiation and proliferation.

3. FOXO Transcription Factors: Modulation of genes related to stress resistance, metabolism, and longevity.

4. mTOR Signaling: Involved in cell growth, protein synthesis, and autophagy regulation.

••••• Reciprocal Response:

There is a Reciprocal Response between IGF-1 pathway and Klotho. The inhibitory action of Klotho on IGF-1 receptor can reduce the proliferative and metabolic actions of IGF-1. Conversely, excessive IGF-1 signaling might suppress Klotho expression, tipping the balance towards growth and away from longevity.

•••••• Diseases Associated with this Pathway:

1. Cancers: Overactive IGF-1 signaling can promote tumorigenesis and tumor progression.

2. Acromegaly: Overproduction of IGF-1 due to pituitary adenomas.

3. Cardiovascular Diseases: IGF-1's role in vascular function can impact heart health.

4. Osteoporosis: IGF-1 plays a role in bone metabolism.

The inhibitory effect of Klotho on the IGF-1 pathway can have protective implications against these conditions.

••••••• Active Interventional Agents:

1. Peptides: IGF-1 and its binding proteins.

2. Small Molecules: Inhibitors targeting the IGF-1 receptor or downstream signaling components.

3. Hormones: Growth hormone (indirectly increases IGF-1 levels).

4. Plant-Derived Compounds: Some compounds, like epigallocatechin gallate (EGCG), can influence IGF-1 signaling.

5. Drugs: Agents like linsitinib, targeting the IGF-1 receptor.

References:

[2007] Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17

[⬇︎][ INF-ƴ ][⬇︎]

Interferon Gamma (INF-ƴ) Pathway

This pathway potentially Down-Regulates Klotho

Klotho Down-Regulates this Pathway

•(12)•

• Impact on Aging:

The Interferon Gamma Pathway (INF-ƴ Pathway) primarily mediates immune responses, specifically in promoting macrophage activation and facilitating adaptive immunity. Chronic activation of the INF-ƴ pathway is associated with inflammatory conditions, which are recognized contributors to the aging process and age-related pathologies. Sustained inflammation (sometimes referred to as inflammaging) can promote cellular senescence, tissue dysfunction, and degeneration.

Klotho has anti-inflammatory properties and may counteract the pro-inflammatory effects of the INF-ƴ pathway, thus potentially influencing the aging process.

•• Pathway <•> Klotho:

The INF-ƴ pathway Down-Regulates Klotho. Pro-inflammatory conditions, driven by factors like INF-ƴ, tend to suppress Klotho expression, which may exacerbate the inflammatory state and further promote aging-related changes.

••• Klotho <•> Pathway:

Klotho Down-Regulates the INF-ƴ pathway. Klotho can act as a negative regulator of inflammation. By suppressing various inflammatory pathways, including the INF-ƴ-mediated responses, Klotho may contribute to reduced tissue damage and cellular senescence, supporting healthy aging.

•••• Downstream Pathways:

Upon activation by INF-ƴ, several pathways are triggered:

1. JAK-STAT Signaling Pathway: Mediating gene transcription associated with immune responses.

2. NF-κB Pathway: A major pro-inflammatory signaling cascade.

3. MAPK Pathway: Involved in cellular proliferation, differentiation, and survival.

4. iNOS Production: Inducing nitric oxide synthesis, which has antimicrobial properties but can also induce cellular damage in excess.

••••• Reciprocal Response:

There is a Reciprocal Response between the INF-ƴ pathway and Klotho. As Klotho suppresses INF-ƴ-mediated inflammatory responses, reduced Klotho levels due to age or other factors might make tissues more susceptible to inflammation and its associated damages.

•••••• Diseases Associated with this Pathway:

1. Autoimmune Diseases: Such as multiple sclerosis and rheumatoid arthritis where INF-ƴ plays a role in pathogenesis.

2. Chronic Inflammatory Diseases: Like Crohn’s disease and ulcerative colitis.

3. Infectious Diseases: Where INF-ƴ is crucial for defense against intracellular pathogens.

4. Cancers: INF-ƴ has complex roles in cancer, either inhibiting or promoting tumor growth depending on the context.

Klotho's anti-inflammatory effects might provide therapeutic benefits in these conditions.

••••••• Active Interventional Agents:

1. Proteins/Peptides: INF-ƴ itself or its neutralizing antibodies.

2. Small Molecules: Inhibitors targeting JAK-STAT signaling or NF-κB activation.

3. Hormones: Glucocorticoids which have anti-inflammatory effects.

4. Plant-Derived Compounds: Curcumin and resveratrol, known for their anti-inflammatory properties.

5. Drugs: Agents like tofacitinib and baricitinib, targeting the JAK-STAT pathway.

References:

[⬇︎][ IL-6 ][⬇︎]

Interleukin-6 (IL-6)

This pathway Down-Regulates Klotho

Klotho Down-Regulates this Pathway

•(13)•

• Impact on Aging:

The Interleukin-6 (IL-6) pathway is involved in mediating inflammatory responses, immune regulation, and hematopoiesis. Elevated levels of IL-6 are associated with aging and chronic inflammatory conditions, often referred to as "inflammaging." Persistent IL-6 activity can contribute to systemic inflammation, promoting cellular senescence, tissue dysfunction, and the progression of age-related diseases.

Klotho is known to exert anti-inflammatory effects and might attenuate the pro-inflammatory properties of the IL-6 pathway, thereby influencing the aging process.

•• Pathway <•> Klotho:

The IL-6 pathway Down-Regulates Klotho. Chronic activation of the IL-6 pathway, especially in inflammatory conditions, has been linked to reduced Klotho expression. This suppression of Klotho can further enhance inflammatory responses and promote age-associated changes.

••• Klotho <•> Pathway:

Klotho Down-Regulates the IL-6 pathway. Klotho can act as a negative regulator of inflammation, including suppression of IL-6-mediated responses. By inhibiting IL-6 and its downstream signaling, Klotho may help reduce inflammation-induced damage and aging effects.

•••• Downstream Pathways:

IL-6 activates several downstream pathways, including:

1. JAK-STAT Signaling Pathway: Critical for immune cell differentiation and pro-inflammatory gene transcription.

2. MAPK Pathway: Involved in cell proliferation, differentiation, and survival.

3. PI3K-Akt Pathway: Regulating cell growth and survival.

4. NF-κB Pathway: Another major pro-inflammatory signaling cascade.

••••• Reciprocal Response:

There is a Reciprocal Response between the IL-6 pathway and Klotho. Reduced Klotho expression can potentiate IL-6-mediated inflammatory responses, while Klotho's anti-inflammatory effects can help counterbalance IL-6-driven inflammation, setting up a regulatory feedback loop.

•••••• Diseases Associated with this Pathway:

1. Rheumatoid Arthritis: Elevated IL-6 levels contribute to joint inflammation and damage.

2. Cardiovascular Diseases: IL-6 is implicated in atherosclerosis and other cardiac pathologies.

3. Cancers: IL-6 can promote tumor growth, angiogenesis, and metastasis.

4. Autoimmune Diseases: Where IL-6 contributes to immune dysregulation.

5. Osteoporosis: IL-6 affects bone metabolism, leading to bone resorption.

Klotho's potential inhibitory impact on the IL-6 pathway might offer protective benefits in these conditions.

••••••• Active Interventional Agents:

1. Antibodies: Tocilizumab and sarilumab, which target the IL-6 receptor.

2. Small Molecules: JAK inhibitors like tofacitinib that impact the JAK-STAT pathway downstream of IL-6 signaling.

3. Hormones: Glucocorticoids which are broad-spectrum anti-inflammatory agents.

4. Plant-Derived Compounds: Curcumin and resveratrol, known for their anti-inflammatory and antioxidative properties.

5. Peptides: Directly targeting IL-6 or its associated signaling molecules.

References:

[2014] Association of Klotho and interleukin 6 gene polymorphisms with aging in Han Chinese population

[⬆︎⬇︎][ KL ][⬆︎⬇︎][₪]

Klotho Signaling Pathway (KLP)

This pathway potentially Up-Regulates Klotho

Klotho Up-Regulates this Pathway

•(14)•

• Overview:

The Klotho gene encodes a type-I membrane protein related to beta-glucuronidases. Reduced production of this protein has been linked to shortened lifespan, while increased production has been associated with an extended lifespan. The Klotho protein can influence multiple signaling pathways, but one of its most notable roles is as a co-receptor for Fibroblast Growth Factor 23 (FGF23), which regulates phosphate homeostasis and vitamin D metabolism.

FGF23-Klotho signaling pathway (most commonly abbreviated as the FGF23-KL pathway) is significantly impacted by Klotho.

Klotho Upregulates the FGF23-KL pathway.

• Impact on Aging:

The Klotho signaling pathway (KLP) plays a pivotal role in various physiological processes related to aging. Klotho (KL), primarily existing as membrane-bound alpha Klotho and soluble Klotho forms, acts as an anti-aging protein. Its diminished expression is linked with age-related pathologies and reduced lifespan, while overexpression can extend lifespan in model organisms. It is associated with regulation of mineral metabolism, suppression of oxidative stress, and the modulation of insulin/IGF-1 signaling, which has direct implications on aging.

Klotho interacts with numerous other pathways, potentially mediating their impacts on aging and aging-related diseases.

•• Pathway <•> Klotho:

Given that this is about the Klotho pathway itself, Klotho inherently serves as the core regulator of its pathway. It can be both the influencer and influenced entity in the context of its signaling.

••• Klotho <•> Pathway:

The same point applies here. Klotho is central to its signaling cascade, meaning it intrinsically modulates its downstream effects and can be modulated by upstream regulators or feedback mechanisms within its own pathway.

•••• Downstream Pathways:

Klotho influences a range of downstream pathways, including:

1. Wnt Signaling: Klotho suppresses this pathway, preventing osteoporosis, vascular calcification, and renal fibrosis.

2. FGF23 Signaling: A core interaction, with Klotho serving as a co-receptor for FGF23, influencing phosphate metabolism.

3. Insulin/IGF-1 Signaling: Klotho inhibits this pathway, thereby improving stress resistance and longevity.

4. TRPV5 Calcium Channel Regulation: Enhancing calcium reabsorption in kidneys.

••••• Reciprocal Response:

Within its own pathway, Klotho has intricate feedback loops. For instance, factors that decrease Klotho expression can exacerbate age-related pathologies, while factors enhancing Klotho expression can delay them.

•••••• Diseases Associated with this Pathway:

1. Chronic Kidney Disease (CKD): Altered Klotho-FGF23 interactions impact mineral metabolism.

2. Cardiovascular Diseases: Low Klotho levels are linked with endothelial dysfunction and atherosclerosis.

3. Osteoporosis: Due to aberrant Wnt and mineral metabolism signaling.

4. Neurodegenerative Diseases: Reduced Klotho levels are associated with cognitive decline.

Restoring or enhancing Klotho expression could have potential therapeutic effects on these conditions.

••••••• Active Interventional Agents:

1. Small Molecules: Rapamycin, Resveratrol, Statins, SRT1720, All-trans retinoic acid (ATRA): Compounds that can elevate endogenous Klotho levels.

2. Peptides: Mimetics resembling the Klotho structure.

3. Vitamins: Vitamin D has been implicated in Klotho regulation.

4. Hormones: Certain hormones or their analogs may influence Klotho levels.

5. Genetic and Epigenetic Modulators: Potential for CRISPR or other gene therapies to enhance Klotho expression or activity.

References:

[2022] Aging-suppressor Klotho- Prospects in diagnostics and therapeutics

[⬆︎][ mTOR ][⬇︎][₪]

Mammalian Target of Rapamycin pathway (mTOR)

This pathway Up-Regulates Klotho

Klotho Down-Regulates this Pathway

•(15)•

• Impact on Aging:

1. The mTOR pathway is a central regulator of cell growth, proliferation, survival, and metabolism. Dysregulation of this pathway has been linked to various age-related diseases, including cancer, neurodegenerative diseases, and type 2 diabetes. Chronic activation of mTOR signaling can promote cellular senescence and aging.

2. Klotho has been reported to negatively regulate the mTOR pathway. This can be part of the protective effect of Klotho against age-related pathologies, as reduced mTOR signaling has been associated with increased lifespan in various organisms.

•• Pathway <•> Klotho:

The mTOR pathway is down-regulated by Klotho. This interaction can lead to enhanced autophagy, reduced cellular senescence, and potential protective effects against age-related diseases.

••• Klotho <•> Pathway:

Klotho's expression can be influenced by the mTOR pathway, particularly in situations where the mTOR pathway is inhibited. Inhibition of mTOR has been associated with increased Klotho expression.

•••• Downstream Pathways:

The mTOR pathway influences several downstream processes, including:

• Protein synthesis (via the S6 kinase)

• Lipogenesis

• Autophagy inhibition

• Cell growth and proliferation

• Ribosome biogenesis

• Mitochondrial biogenesis and function.

••••• Reciprocal Response:

There's evidence that inhibiting the mTOR pathway can lead to an upregulation of Klotho expression, suggesting a potential reciprocal regulatory relationship.

•••••• Diseases Associated with this Pathway:

The mTOR pathway is implicated in:

• Cancers

• Neurodegenerative diseases (like Alzheimer's and Parkinson's)

• Type 2 diabetes

• Age-related cardiac hypertrophy

• Age-related declines in stem cell function. Klotho's downregulation of the mTOR pathway might mitigate the risks or progression of some of these diseases.

••••••• Active Interventional Agents:

Many biologically active substances (from the AAIR) can influence the mTOR pathway:

• Rapamycin (and its analogs): Inhibits mTOR, extending lifespan in several organisms.

• Nutrients (like amino acids and glucose): Can activate mTOR.

• Resveratrol: Has been proposed to modulate mTOR activity.

• Metformin: An anti-diabetic drug that can influence the mTOR pathway.

• Klotho: As discussed, Klotho can negatively regulate mTOR signaling.

References:

[2023] Rapamycin treatment increases survival, autophagy biomarkers and expression of the anti-aging klotho protein in elderly mice

[⬇︎][ MAPK ][⬇︎]

Mitogen-Activated Protein Kinase Pathway (MAPK)

This pathway Down-Regulates Klotho

Klotho Down-Regulates this Pathway

•(16)•

• Impact on Aging:

1. The MAPK pathway plays a crucial role in various cellular processes, including growth, differentiation, and response to external stresses. Dysregulation of the MAPK pathway has been implicated in cellular senescence, inflammation, and the onset of various age-related diseases.

2. Klotho acts as an antagonist to the MAPK pathway, specifically the ERK1/2 signaling. By inhibiting the MAPK pathway, Klotho may contribute to reduced cellular senescence and aging-related changes.

•• Pathway <•> Klotho:

The MAPK pathway is down-regulated by Klotho. This interaction results in reduced cellular proliferation and inflammation, which could potentially counteract age-related pathologies.

••• Klotho <•> Pathway:

While Klotho down-regulates the MAPK pathway, certain stress factors or conditions might lead to MAPK-mediated reduction of Klotho expression, pointing to a reciprocal influence.

•••• Downstream Pathways:

The MAPK pathway comprises three main cascades: ERK, JNK, and p38 MAPK. These pathways control various processes, including:

• Cell proliferation

• Apoptosis

• Inflammation

• DNA damage response

• Cellular differentiation

••••• Reciprocal Response:

Some studies suggest that activated MAPK pathway components, particularly under stress conditions, can downregulate Klotho expression. This implies a potential feedback mechanism where elevated MAPK signaling decreases Klotho levels.

•••••• Diseases Associated with this Pathway:

The MAPK pathway is associated with:

• Various cancers due to unchecked cellular proliferation

• Inflammatory diseases

• Neurodegenerative conditions like Alzheimer's Disease, where MAPKs might contribute to neuronal death

• Cardiovascular diseases The inhibitory effect of Klotho on the MAPK pathway could, in theory, offer protection against some of these diseases.

••••••• Active Interventional Agents:

Several substances from the AAIR can modulate the MAPK pathway:

• Klotho: As previously mentioned, it inhibits the MAPK pathway.

• EGF (Epidermal Growth Factor): Activates the ERK MAPK pathway.

• UV radiation: Can activate the JNK and p38 MAPK pathways.

• Various small molecule inhibitors targeting components of the MAPK pathway, such as MEK inhibitors.

• Phytochemicals like curcumin and resveratrol have shown effects on MAPK signaling in some studies.

References:

[⬆︎][ Nrf2 ][⬆︎][₪]

The Nuclear factor erythroid 2-related factor 2 pathway (Nrf2)

This pathway directly Up-Regulates Klotho

Klotho Up-Regulates this Pathway

•(17)•

• Impact on Aging:

1. The Nrf2 pathway is pivotal for maintaining cellular redox homeostasis by regulating the expression of antioxidant proteins that protect against oxidative damage. Enhanced Nrf2 activity has been linked to increased resistance to oxidative stress, reduced inflammation, and improved mitochondrial function, all of which are pivotal in counteracting cellular aging processes.

2. Klotho is known to stimulate Nrf2 activation. Thus, Klotho's interaction with the Nrf2 pathway further bolsters cellular defense mechanisms against oxidative stress, which is one of the primary contributors to aging and age-related diseases.

3. [₪] Nrf2 up-regulation down regulates NF-κß, conversely the up-regulation of NF-κß down regulates Nrf2.

   • [2023] Nrf2 signaling in diabetic nephropathy, cardiomyopathy and neuropathy- Therapeutic targeting, challenges and future prospective

•• Pathway <•> Klotho:

The Nrf2 pathway is up-regulated by Klotho. This interaction strengthens cellular antioxidant defenses, reduces inflammation, and potentially mitigates age-associated cellular damage.

••• Klotho <•> Pathway:

Klotho can up-regulate the Nrf2 pathway, enhancing the cell's defensive response against oxidative stress. This action underscores Klotho's protective role against oxidative damage and potential aging processes.

•••• Downstream Pathways:

Upon activation, Nrf2 translocates to the nucleus, where it binds to antioxidant response elements (AREs). This binding prompts the transcription of a suite of genes encoding for:

• Antioxidant enzymes (like superoxide dismutase and catalase)

• Detoxifying enzymes (like glutathione S-transferases)

• Drug efflux pumps

• Stress response proteins

••••• Reciprocal Response:

While Klotho stimulates the Nrf2 pathway, chronic oxidative stress, which down-regulates Klotho, can impair Nrf2 activity, suggesting a potential feedback loop where reduced Klotho and Nrf2 activity might exacerbate cellular damage.

•••••• Diseases Associated with this Pathway:

The Nrf2 pathway has implications in:

• Neurodegenerative diseases like Alzheimer's and Parkinson's, where enhanced Nrf2 activity might offer neuroprotection.

• Cardiovascular diseases: Nrf2's antioxidative properties can protect against vascular damage.

• Chronic inflammatory diseases

• Cancers: While Nrf2 offers protection against carcinogens, its dysregulation can aid cancer cell survival. Klotho's upregulation of the Nrf2 pathway can potentially offer therapeutic benefits in these contexts.

••••••• Active Interventional Agents:

Numerous agents from the AAIR can modulate the Nrf2 pathway:

• Klotho: As discussed, it up-regulates the Nrf2 pathway.

• Sulforaphane (found in broccoli): A potent Nrf2 activator.

• Curcumin: Can activate the Nrf2 pathway, boosting antioxidative defenses.

• Resveratrol: Shows potential in Nrf2 activation.

• Tert-butylhydroquinone (tBHQ) and Dimethyl fumarate (DMF): Synthetic Nrf2 activators.

Given the protective role of the Nrf2 pathway in cellular health, modulating its activity has therapeutic potential. However, achieving a balanced activation (avoiding over-activation) is crucial, as excessive Nrf2 can be detrimental, particularly in the context of cancer. Always consult scientific literature and experts when considering interventions targeting this pathway.

References:

[2014] Screening of Natural Compounds as Activators of the Keap1- Nrf2 Pathway

[2016] Sulforaphane improves the bronchoprotective response in asthmatics through Nrf2-mediated gene pathways.pdf alias

[2017] Klotho protects the heart from hyperglycemia-induced injury by inactivating ROS and NF-κB-mediated inflammation both in vitro and in vivo

[2019] Understanding the role of the cytoprotective transcription factor nuclear factor erythroid 2-related factor 2—lessons from evolution, the animal kingdom and rare progeroid syndromes

[2019] The angiotensin‐(1‐7)/Mas receptor axis protects from endothelial cell senescence via klotho and Nrf2 activation

[⬇︎][ NF-κß ][⬇︎]

Nuclear factor-kappa Beta (Light-chain-enhancer of activated B cells) pathway, (NF-κB)

This pathway Down-Regulates Klotho

Klotho protein inhibits (Down Regulates) this pathway

•(18)•

• Impact on Aging:

1. NF-κB is a critical regulator of immune responses, inflammation, cellular growth, and survival. Aberrant activation of the NF-κB pathway is linked to chronic inflammation, a major driver of aging, known as inflammaging. As such, sustained NF-κB activation has been correlated with a variety of age-related diseases.

2. Klotho is suggested to inhibit the activation of NF-κB. Thus, Klotho's modulation of the NF-κB pathway may play a role in suppressing chronic inflammation, potentially mitigating its contributions to aging and age-associated pathologies.

•• Pathway <•> Klotho:

The NF-κB pathway is down-regulated by Klotho. This interaction can mitigate inflammatory responses, possibly slowing down inflammaging and its detrimental impacts on cellular and tissue function.

••• Klotho <•> Pathway:

Klotho can down-regulate the NF-κB pathway, which implies a protective role of Klotho against chronic inflammation and its associated age-related cellular damage and diseases.

•••• Downstream Pathways:

When activated, NF-κB translocates to the nucleus and induces the transcription of various genes, including those involved in:

• Inflammatory cytokine production (like TNF-α, IL-1, and IL-6)

• Cell survival and proliferation (such as Bcl-2 and cyclin D1)

• Immune responses

••••• Reciprocal Response:

While Klotho can suppress the NF-κB pathway, chronic inflammation and associated cellular stressors might down-regulate Klotho expression, suggesting a potential negative feedback loop where persistent inflammation could compromise Klotho's protective roles.

•••••• Diseases Associated with this Pathway:

The NF-κB pathway plays roles in:

• Autoimmune diseases: Given its regulation of immune responses.

• Neurodegenerative diseases: Through its involvement in chronic inflammation.

• Cardiovascular diseases: Linked to vascular inflammation.

• Cancers: As it can promote cell survival and proliferation. Klotho's inhibition of NF-κB might have therapeutic implications in these contexts.

••••••• Active Interventional Agents:

Several agents from the AAIR can influence the NF-κB pathway:

• Klotho: As discussed, it down-regulates the NF-κB pathway.

• Curcumin: Known to inhibit NF-κB activation.

• Omega-3 fatty acids: Can suppress NF-κB activity, reducing inflammation.

• Resveratrol: Demonstrates potential inhibitory effects on NF-κB.

• Green tea polyphenols (e.g., EGCG): Inhibit NF-κB activation.

Given the pivotal role of the NF-κB pathway in inflammation and its associated diseases, modulating its activity is of therapeutic interest. Balancing its modulation is crucial, as NF-κB also plays essential roles in normal immune function. Always refer to scientific literature and consult with experts when considering interventions targeting this pathway.

References:

[2011] The Inflammatory Cytokines TWEAK and TNFα Reduce Renal Klotho Expression through NFκB

[⬆︎][ PPAR-ƴ ][⬆︎][₪]

Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ)

This pathway Up-Regulates Klotho

Klotho Up-Regulates this Pathway

•(19)•

• Impact on Aging:

1. PPAR-γ is a nuclear receptor that plays a central role in adipocyte differentiation, glucose metabolism, and regulation of inflammatory responses. Aging is often accompanied by altered metabolic processes and chronic low-level inflammation. PPAR-γ, by modulating metabolic and inflammatory pathways, can influence aging and age-related diseases.

2. Klotho has been reported to enhance the transcriptional activity of PPAR-γ, suggesting that the beneficial effects of Klotho on aging might be partially mediated by its interaction with PPAR-γ, particularly in the context of metabolic regulation and inflammation suppression.

•• Pathway <•> Klotho:

PPAR-γ is up-regulated by Klotho. This interaction underscores a potential mechanism by which Klotho can improve metabolic function and reduce inflammation, both critical aspects of healthy aging.

••• Klotho <•> Pathway:

Klotho up-regulates the PPAR-γ pathway, suggesting a protective effect of Klotho in metabolic regulation and inflammatory control, which could consequently impact the aging process.

•••• Downstream Pathways:

Activation of PPAR-γ induces transcription of various genes involved in:

• Lipid uptake and storage

• Adipocyte differentiation

• Insulin sensitivity

• Anti-inflammatory processes by inhibiting transcription factors like NF-κB

••••• Reciprocal Response:

While there's evidence that Klotho up-regulates PPAR-γ, the feedback mechanism of PPAR-γ on Klotho levels is not as well-established. However, since PPAR-γ modulates inflammation, which can impact Klotho levels, there might be indirect regulatory interactions.

•••••• Diseases Associated with this Pathway:

PPAR-γ is implicated in:

• Metabolic disorders: Including type 2 diabetes due to its role in insulin sensitivity.

• Cardiovascular diseases: Given its involvement in lipid metabolism and inflammation.

• Neurodegenerative diseases: Via its anti-inflammatory properties. Klotho's enhancement of PPAR-γ activity can potentially offer therapeutic benefits in these contexts.

••••••• Active Interventional Agents:

Various agents from the AAIR can influence the PPAR-γ pathway:

• Thiazolidinediones (TZDs): A class of drugs used for type 2 diabetes that act as PPAR-γ agonists.

• Klotho: As discussed, it up-regulates PPAR-γ.

• Omega-3 fatty acids: Have been reported to activate PPAR-γ.

• Curcumin: Shows potential PPAR-γ agonistic activity.

• Berberine: Demonstrates potential in activating PPAR-γ.

References:

[⬇︎][ PGC-1α ][⬆︎]

Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha Pathway; (PGC-1α)

This pathway does not modulate Klotho

Klotho Up-Regulates this Pathway

(20)

• Impact on Aging:

1. PGC-1α is a transcriptional coactivator that plays a pivotal role in regulating mitochondrial biogenesis, oxidative metabolism, and adaptive thermogenesis. Given that mitochondrial dysfunction is closely linked with aging, PGC-1α's role in promoting mitochondrial health suggests it has an influence on the aging process.

2. While there is limited direct evidence on the interaction between PGC-1α and Klotho, it's notable that both are involved in pathways that mitigate oxidative stress and inflammation, key components of the aging process. The synergy or interactions between these two may have implications in cellular longevity and vitality.

•• Pathway <•> Klotho:

There isn't conclusive evidence directly linking Klotho and PGC-1α. However, given their overlapping roles in modulating oxidative stress and inflammation, it's conceivable there might be potential interactions worth exploring in future research.

••• Klotho <•> Pathway:

Again, while there isn't direct evidence of Klotho modulating PGC-1α, both are involved in pathways that promote cellular resilience and oppose aging-related decline, suggesting potential interplay that would be of interest for future investigations.

•••• Downstream Pathways:

PGC-1α activates a number of downstream pathways, including:

• NRF1 and NRF2: Promoting mitochondrial biogenesis.

• FOXO3: Involved in cellular stress resistance.

• SIRT1: Sirtuin pathway associated with cellular longevity and metabolism.

••••• Reciprocal Response:

There is no direct evidence on PGC-1α's influence on Klotho levels or vice versa. However, both influence protective cellular pathways that mitigate age-related decline.

•••••• Diseases Associated with this Pathway:

PGC-1α is associated with:

• Metabolic Disorders: Its role in glucose and lipid metabolism makes it a target in type 2 diabetes and obesity.

• Neurodegenerative Diseases: Given its role in mitochondrial health, PGC-1α is explored in Parkinson's and Alzheimer's disease contexts.

• Cardiac Diseases: Due to its role in oxidative metabolism and mitochondrial function in heart cells.

••••••• Active Interventional Agents:

AAIR agents influencing PGC-1α include:

• Resveratrol: Found in grapes, it is known to upregulate PGC-1α via SIRT1 activation.

• Metformin: An antidiabetic drug, it indirectly influences PGC-1α.

• Exercise: Physical activity is known to enhance PGC-1α levels, promoting mitochondrial biogenesis.

• Cold Exposure: Increases PGC-1α levels to enhance thermogenesis.

References:

[⬇︎][ PI3K/Akt ][⬇︎]

Phosphatidylinositol 3-Kinase/Protein Kinase B pathway (PI3K/Akt)

This pathway Down-Regulates Klotho

Klotho Down-Regulates this Pathway

•(21)•

• Impact on Aging:

1. PI3K/Akt is a critical cell-signaling pathway involved in regulating the cell cycle. It has roles in cellular quiescence, proliferation, cancer, and longevity. Dysregulation of this pathway has been implicated in a number of diseases including cancer, diabetes, cardiovascular disease, and neurological diseases—all of which have implications in aging.

2. The interaction between PI3K/Akt and Klotho is quite direct. Klotho has been shown to inhibit the PI3K/Akt signaling. This inhibition can lead to increased cellular stress resistance, a key factor in the longevity-promoting effects of Klotho.

•• Pathway <•> Klotho:

PI3K/Akt can be inhibited by Klotho, especially in renal cells. This inhibition by Klotho has been suggested to be protective against oxidative stress and cellular senescence, thus promoting longevity and counteracting certain age-related pathologies.

••• Klotho <•> Pathway:

Klotho's inhibitory effect on the PI3K/Akt pathway signifies a protective role, with potential implications for aging. Klotho deficiency has been associated with signs of accelerated aging, while its overexpression promotes longevity in some model organisms.

•••• Downstream Pathways:

Downstream of PI3K/Akt are a variety of effectors including:

• mTORC1: A major regulator of cellular growth and metabolism.

• FOXO transcription factors: Which control genes involved in stress resistance, metabolism, cell cycle arrest, and apoptosis.

• GSK-3β: Glycogen synthase kinase 3 beta, involved in numerous cellular processes including glycogen metabolism and cellular signaling.

••••• Reciprocal Response:

The inhibition of PI3K/Akt by Klotho hints at a potential feedback mechanism, but direct reciprocal regulation of Klotho by PI3K/Akt hasn't been extensively documented.

•••••• Diseases Associated with this Pathway:

The PI3K/Akt pathway's dysregulation is implicated in:

• Cancer: Due to its role in cell proliferation and survival.

• Diabetes: From its involvement in insulin signaling.

• Neurological Diseases: Such as Alzheimer's, given the pathway's role in neuronal survival.

• Cardiovascular Diseases: Due to its involvement in vascular endothelial growth factor (VEGF) signaling and endothelial cell survival.

••••••• Active Interventional Agents:

AAIR agents influencing PI3K/Akt include:

• Metformin: An antidiabetic drug, it can affect this pathway indirectly.

• Resveratrol: Known to modulate the PI3K/Akt signaling.

• Curcumin: Found in turmeric, it has inhibitory effects on PI3K/Akt.

• Green tea extracts: Contains compounds like EGCG that can modulate this pathway.

• Wortmannin & LY294002: Specific pharmacological inhibitors of PI3K.

The PI3K/Akt pathway's modulation offers potential therapeutic avenues for a variety of diseases, especially age-related ones. As always, direct consultation with experts and reference to scientific literature is essential when considering interventions.

References:

[⬆︎][ PKC ][⬇︎]

Protein Kinase C (PKC)

This pathway Up-Regulates Klotho

Klotho Down-Regulates this Pathway

•(22)•

• Impact on Aging:

1. PKC is a family of protein kinases involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues. Dysregulation of PKC has been linked to diseases such as cancer, diabetes, and neurodegenerative conditions which have significant implications for aging.

2. Interaction between PKC and Klotho is nuanced. Klotho has been reported to inhibit certain PKC isoforms, suggesting that it can influence cellular processes modulated by PKC and thus impact aging.

•• Pathway <•> Klotho:

Certain PKC isoforms can be influenced by Klotho. Klotho's role in calcium regulation might indirectly modulate PKC activity, as PKC is activated by increases in diacylglycerol (DAG) and calcium. By inhibiting certain PKC isoforms, Klotho can play a role in modulating cellular processes linked to longevity and age-associated pathologies.

••• Klotho <•> Pathway:

The specific interplay between Klotho and PKC is not thoroughly detailed in literature. However, given Klotho's inhibitory influence on certain PKC isoforms, it can be speculated that Klotho could act as a negative regulator of PKC-mediated processes.

•••• Downstream Pathways:

PKC influences various cellular processes and pathways:

• NF-κB signaling: Implicated in inflammation and immune responses.

• MAPK pathway: Involved in cell growth, differentiation, and survival.

• JAK/STAT pathway: Implicated in numerous cellular functions from growth to immunity.

••••• Reciprocal Response:

While Klotho's inhibitory effect on PKC hints at a dynamic interaction, explicit feedback mechanisms where PKC influences Klotho levels or function remain to be robustly documented.

•••••• Diseases Associated with this Pathway:

Dysregulation of PKC is implicated in:

• Cancer: Owing to its involvement in cell proliferation and apoptosis.

• Diabetes: Through its role in insulin signaling and glucose metabolism.

• Neurodegenerative Diseases: Such as Alzheimer's due to PKC's role in neuronal signaling.

• Cardiac Diseases: PKC has roles in cardiomyocyte function and vascular response.

••••••• Active Interventional Agents:

AAIR agents influencing PKC include:

• Bryostatin-1: Known to modulate PKC activity.

• Statins: These can inhibit PKC in certain contexts.

• Curcumin: Has inhibitory effects on PKC.

• Phorbol esters: These are classic activators of certain PKC isoforms.

Modulation of PKC is a potential therapeutic target for many diseases, especially those related to aging. As with other pathways, in-depth understanding and consultation with specialists is crucial when considering therapeutic interventions based on PKC.

References:

[⬆︎][ ROMK1 ][U]

Renal Outer Medullary Potassium Channel (ROMK1)

This pathway Up-Regulates Klotho

Unknown if Klotho Down-Regulates this Pathway

•(23)•

• Impact on Aging:

1. ROMK1, a member of the inwardly rectifying potassium channel family, is pivotal for potassium recycling in the kidney's nephron and plays a crucial role in maintaining potassium balance. Dysregulation of potassium balance can impact heart function, muscle function, and nerve transmission. Thus, maintaining proper potassium homeostasis is vital for healthy aging.

2. Klotho enhances the surface expression of ROMK1 channels, indicating a potential collaborative role in the regulation of potassium homeostasis and thus in the aging process.

•• Pathway <•> Klotho:

Klotho has been shown to directly stimulate ROMK1 channels by increasing their expression on the cell surface. The precise mechanism is not fully elucidated, but it's thought that Klotho may stabilize ROMK1 on the cell membrane, leading to enhanced potassium secretion.

••• Klotho <•> Pathway:

ROMK1 function and its relation to potassium balance have downstream implications on various processes related to aging. Whether ROMK1 has any direct influence on Klotho expression or activity is not well-documented.

•••• Downstream Pathways:

ROMK1's primary role lies in potassium homeostasis. Disruptions to this can affect:

• Cardiac Function: Potassium is key in repolarizing cardiac cells.

• Neuromuscular Function: Potassium plays a role in nerve transmission and muscle contraction.

••••• Reciprocal Response:

Current literature primarily discusses Klotho's influence on ROMK1 but doesn't provide conclusive evidence on any feedback mechanism where ROMK1 might influence Klotho expression or function.

•••••• Diseases Associated with this Pathway:

Disruptions in ROMK1 are linked to:

• Bartter syndrome: A renal disorder leading to low blood potassium levels.

• Hyperkalemia or Hypokalemia: High or low blood potassium levels respectively, affecting cardiac and neuromuscular functions.

••••••• Active Interventional Agents:

There are a few agents and drugs known to influence ROMK1:

• Loop diuretics: Like furosemide and bumetanide, can inhibit ROMK1.

• Klotho: As mentioned, it can enhance ROMK1 expression on the cell surface.

Maintaining potassium balance is essential, and any therapeutic interventions in this pathway need rigorous understanding and monitoring.

[⬇︎][ RAS ][⬇︎][₪]

Renin-Angiotensin System (RAS)

This Pathway Can Modulate Klotho

Klotho Downregulates this Pathway

•(24)•

• Impact on Aging:

1. The Renin-Angiotensin System (RAS) plays a crucial role in the regulation of blood pressure, fluid balance, and electrolyte homeostasis. Dysregulation of RAS is associated with the development of hypertension, cardiovascular diseases, and kidney diseases, which are all major risk factors for accelerated aging.

2. Klotho has been shown to negatively regulate the RAS by suppressing renin expression and secretion. Reduced Klotho expression may lead to RAS overactivation, contributing to age-related diseases.

•• Pathway <•> Klotho:

Klotho down-regulates the RAS. Reduced Klotho levels can lead to the overactivation of the RAS, which is a potential pathogenic mechanism in hypertension and renal disease. The implications for aging are significant because of the systemic effects of RAS overactivation, including vascular dysfunction and increased oxidative stress.

••• Klotho <•> Pathway:

Overactivation of the RAS reduces the expression and secretion of Klotho. Angiotensin II, a product of the RAS, has been found to reduce Klotho expression in renal cells, which could amplify the detrimental effects of RAS overactivation.

•••• Downstream Pathways:

Activation of RAS results in the production of angiotensin II, which acts on various pathways:

• AT1R Activation: Leading to vasoconstriction, increased aldosterone secretion, and increased blood pressure.

• NADPH Oxidase Activation: Producing reactive oxygen species and leading to oxidative stress.

• MAPK Activation: Resulting in cellular growth and proliferation.

••••• Reciprocal Response:

There's a feedback loop in play where the increased activity of the RAS, specifically through angiotensin II, reduces Klotho expression. On the other hand, Klotho can suppress the RAS. This bidirectional interaction can influence the progression of age-related diseases.

•••••• Diseases Associated with this Pathway:

• Hypertension: Overactivity of the RAS contributes to high blood pressure.

• Cardiovascular Diseases: Such as myocardial infarction and stroke.

• Renal Diseases: Including chronic kidney disease and renal fibrosis.

• Metabolic Disorders: Such as insulin resistance.

••••••• Active Interventional Agents:

Several agents target the RAS:

• ACE Inhibitors: Like lisinopril and enalapril, reduce angiotensin II production.

• Angiotensin II Receptor Blockers (ARBs): Such as losartan and valsartan, block the actions of angiotensin II.

• Renin Inhibitors: Like aliskiren, directly inhibit renin, the first step in the RAS.

The RAS is a cornerstone in understanding cardiovascular and renal physiology and pathology, especially in the context of aging. Its interplay with Klotho adds another layer of complexity and therapeutic potential.

References:

•••••••••••••••••••••••••••••••••••••••••••••••••••••••••••

[⬆︎][ SIRT1 ][⬆︎][₪]

Sirtuin 1 Pathway (SIRT1)

This pathway potentially down regulates Klotho

Klotho Up-Regulates this Pathway

•(25)•

• Impact on Aging:

1. SIRT1, a member of the sirtuin family, is an NAD+-dependent deacetylase that plays a pivotal role in various cellular processes, including DNA repair, apoptosis, inflammation, and mitochondrial biogenesis. By modulating these processes, SIRT1 is known to influence lifespan and counteract cellular senescence.

2. Klotho has been shown to increase the expression of SIRT1. This enhances the deacetylase activity of SIRT1, which in turn can delay cellular aging and attenuate age-related pathologies.

•• Pathway <•> Klotho:

Klotho up-regulates the SIRT1 pathway. Elevated Klotho levels lead to increased SIRT1 activity, promoting cellular health and resistance against oxidative stress. Such regulation can counteract age-related cellular dysfunction.

••• Klotho <•> Pathway:

Activation of the SIRT1 pathway appears to increase the expression and secretion of Klotho. This suggests a reciprocal relationship where Klotho and SIRT1 mutually enhance each other's functions to combat aging and its associated disorders.

•••• Downstream Pathways:

SIRT1 influences several pathways and processes:

• p53 Deacetylation: Inhibiting cellular senescence and apoptosis.

• NF-κB Deacetylation: Suppressing inflammation.

• PGC-1α Activation: Promoting mitochondrial biogenesis and function.

• FOXO Activation: Modulating stress resistance, metabolism, and lifespan.

••••• Reciprocal Response:

As Klotho increases SIRT1 expression and activity, SIRT1 also seems to elevate Klotho expression. This bidirectional relationship implies a feedback loop that may act as a protective mechanism against age-related diseases.

•••••• Diseases Associated with this Pathway:

• Neurodegenerative Diseases: Like Alzheimer's due to SIRT1's role in neuronal survival.

• Cardiovascular Diseases: As SIRT1 plays a part in endothelial function and inflammation suppression.

• Metabolic Disorders: Including type 2 diabetes, due to the role of SIRT1 in glucose homeostasis and insulin sensitivity.

••••••• Active Interventional Agents:

Several agents can modulate SIRT1 activity:

• Resveratrol: A polyphenol found in red wine known to activate SIRT1.

• SRT1720: A synthetic compound that enhances SIRT1 activity.

• Nicotinamide Mononucleotide (NMN): A precursor of NAD+, which is crucial for SIRT1 activity.

• Nicotinamide Riboside (NR): Another NAD+ precursor known to elevate SIRT1 functions.

The SIRT1 pathway, with its vast influence over many cellular processes related to aging, and its intriguing interplay with Klotho, positions it as an exciting focus for research into aging and age-related diseases.

References:

[⬆︎][ Na+/K+-ATPase ][⬆︎][₪]

Sodium-Potassium Adenosine Triphosphatase Pathway (Na+/K+-ATPase)

This pathway Up-Regulates Klotho

Klotho Up-Regulates this Pathway

•(26)•

• Impact on Aging:

1. Na+/K+-ATPase is an integral membrane protein responsible for maintaining the electrochemical gradient across the cell membrane by pumping three sodium ions out and two potassium ions into the cell. By regulating ion balance, cell volume, and cellular osmolarity, it plays a vital role in various physiological processes, including nerve impulse conduction, muscle contraction, and nutrient absorption. Dysfunction of this pump can lead to cellular senescence and is implicated in various age-related diseases.

2. Klotho enhances the stability and activity of Na+/K+-ATPase. By doing so, Klotho ensures the proper function of various cellular processes, thereby playing a role in healthy aging and prevention of cellular dysfunction.

•• Pathway <•> Klotho:

Klotho up-regulates the Na+/K+-ATPase pathway. Through its action, Klotho ensures the pump functions optimally, which is essential for cellular health and counteracting age-related cellular dysfunction.

••• Klotho <•> Pathway:

Klotho has been found to bind to Na+/K+-ATPase directly, thereby enhancing its stability and function. Thus, Klotho directly modulates this pathway, further underlining its importance in various physiological processes.

•••• Downstream Pathways:

Beyond its primary function, Na+/K+-ATPase also engages in signal transduction processes, particularly through its interaction with Src kinase. It can activate multiple pathways such as:

• MAPK/ERK Pathway: Involved in cell growth and differentiation.

• PI3K/Akt Pathway: Influencing cell survival and growth.

••••• Reciprocal Response:

Klotho's positive impact on Na+/K+-ATPase stability and function suggests that activation of the Na+/K+-ATPase pathway may, in turn, enhance the effects of Klotho. This mutual enhancement emphasizes the potential therapeutic role of both targets in age-related diseases.

•••••• Diseases Associated with this Pathway:

• Cardiovascular Diseases: Resulting from the imbalance in ion homeostasis.

• Neurological Disorders: Due to its role in nerve impulse transmission.

• Kidney Diseases: Given its essential role in maintaining salt and water balance.

••••••• Active Interventional Agents:

Modulators of Na+/K+-ATPase include:

• Cardiac Glycosides: Like digoxin and ouabain which inhibit the pump.

• Klotho: Enhances the stability and activity of the pump.

• Vanadate: Another inhibitor of the pump.

Understanding the interplay between Klotho and Na+/K+-ATPase provides insights into their joint contribution to cellular health and potential therapeutic avenues for age-related disorders.

[⬆︎][ Sp1 ][⬆︎][₪]

Specificity Protein 1 Pathway (Sp1)

This pathway Up-Regulates Klotho

Klotho Up-Regulates this Pathway

•(27)•

• Impact on Aging:

1. Sp1, or Specificity Protein 1, is a transcription factor that binds to GC-rich motifs of many promoters. It regulates the expression of a multitude of genes involved in various cellular processes such as growth, differentiation, DNA repair, and apoptosis. Dysregulation of Sp1-mediated transcription can lead to cellular dysfunction, which is implicated in many diseases, including those associated with aging.

2. The interaction between Klotho and Sp1 is noteworthy because Klotho can affect the Sp1-regulated gene transcription, which in turn can impact cell aging processes and longevity.

•• Pathway <•> Klotho:

Klotho can either up-regulate or down-regulate specific genes where Sp1 acts as a transcription factor. The exact modulation depends on the cellular context and the specific gene involved. In some contexts, Klotho may inhibit Sp1 transcriptional activity, while in others, it may enhance it.

••• Klotho <•> Pathway:

Sp1 can affect the transcription of the Klotho gene itself. The exact interaction can vary, but in some studies, Sp1 has been shown to positively regulate Klotho expression, suggesting a potential feedback loop.

•••• Downstream Pathways:

The impact of Sp1 reaches far and wide due to its role as a transcription factor. A few notable pathways include:

• p53 Pathway: Sp1 can regulate p53, a crucial tumor suppressor and cell cycle regulator.

• TGF-β signaling: Sp1 can be involved in the regulation of TGF-β, which has roles in cell growth and differentiation.

••••• Reciprocal Response:

Given that Sp1 can influence Klotho transcription and Klotho can modulate Sp1 activity, there is potential for a reciprocal regulatory relationship or feedback loop between these two. The nature of this relationship is likely complex and context-dependent.

•••••• Diseases Associated with this Pathway:

• Cancer: Dysregulation of Sp1 can lead to aberrant expression of oncogenes or tumor suppressor genes.

• Neurodegenerative Diseases: Due to its role in neuronal differentiation and survival.

• Cardiovascular Diseases: Through genes that Sp1 regulates associated with vascular function.

••••••• Active Interventional Agents:

Several agents can modulate Sp1 activity, including:

• Mithramycin A: An inhibitor of Sp1 binding to DNA.

• Betulinic Acid: Known to down-regulate Sp1 in some contexts.

• Klotho: Can influence Sp1 transcriptional activity.

Understanding the intricate relationship between Klotho and Sp1 can provide potential therapeutic strategies for aging and age-related diseases.

[⬇︎][ TGF-β ][⬇︎][₪]

Transforming Growth Factor-beta (TGF-β)

This pathway Up-Regulates Klotho

Klotho Up-Regulates this Pathway

•(28)•

• Impact on Aging:

1. TGF-β is a multifunctional cytokine that belongs to a large superfamily of proteins. It plays a pivotal role in cellular functions such as proliferation, differentiation, migration, apoptosis, and extracellular matrix production. Dysregulation of TGF-β signaling has been implicated in several pathological conditions, including fibrosis, cancer, and diseases related to aging.

2. Klotho has been identified as a co-receptor for TGF-β, making it essential in modulating the TGF-β signaling pathway. By influencing this pathway, Klotho can potentially affect cellular processes like fibrosis, which is related to the aging of organs like the kidney and heart.

•• Pathway <•> Klotho:

The TGF-β pathway's signaling can be modulated by Klotho. In particular, Klotho has been shown to inhibit TGF-β signaling, reducing fibrotic processes and potentially counteracting aging-related pathological conditions.

••• Klotho <•> Pathway:

TGF-β can influence Klotho expression. In some cellular contexts, TGF-β decreases the expression of Klotho, which might further enhance aging-related processes or disease states.

•••• Downstream Pathways:

TGF-β signaling affects a multitude of downstream pathways, including:

• SMAD signaling: Classical pathway for TGF-β signal transduction.

• MAPK/ERK pathway: Influences cell growth and differentiation.

• PI3K/Akt pathway: A pathway that can be affected by TGF-β, impacting cell survival and proliferation.

••••• Reciprocal Response:

Given that Klotho can inhibit TGF-β signaling and TGF-β can suppress Klotho expression, there's a potential feedback loop between them. This relationship might be key in understanding certain aging processes and finding therapeutic targets.

•••••• Diseases Associated with this Pathway:

• Fibrosis: TGF-β is a central mediator of fibrotic processes in organs like the kidney, lung, and liver.

• Cancer: Dysregulation of TGF-β signaling can contribute to tumor progression.

• Cardiovascular Diseases: Due to its role in vascular remodeling and cardiac fibrosis.

••••••• Active Interventional Agents:

Several agents can modulate TGF-β activity, including:

• SB431542: An inhibitor of the TGF-β type I receptor ALK5.

• Pirfenidone: An antifibrotic agent that modulates TGF-β.

• Klotho: As previously mentioned, Klotho acts as a modulator of TGF-β signaling.

By comprehending the intricate interplay between Klotho and TGF-β, insights into novel therapeutic approaches for age-related diseases and conditions may emerge.

References:

[2011] Klotho Inhibits Transforming Growth Factor-β(TGF-β1) Signaling and Suppresses Renal Fibrosis and Cancer Metastasis in Mice

[2017] The production of fibroblast growth factor 23 is controlled by TGF-β2

[2023] TGF-β as A Master Regulator of Aging-Associated Tissue Fibrosis

[2023] Circulating α-Klotho Counteracts Transforming Growth Factor-β–Induced Sarcopenia

[⬆︎][ TRPV5 ][~]

Transient Receptor Potential Cation Channel Subfamily V Member 5 Pathway (TRPV5)

Unknown if this pathway modulates Klotho

Klotho Up-Regulates this Pathway

•(29)•

• Impact on Aging:

1. TRPV5 is a calcium-selective channel primarily expressed in the distal convoluted tubules and connecting tubules of the kidney. This channel plays a pivotal role in calcium reabsorption, which is crucial for maintaining calcium homeostasis, bone health, and preventing kidney stone formation. With aging, there can be alterations in calcium metabolism, potentially leading to bone diseases like osteoporosis.

2. Klotho has been shown to upregulate TRPV5 by stabilizing its expression at the plasma membrane, thereby enhancing renal calcium reabsorption. This interaction between Klotho and TRPV5 might influence the aging-related alterations in calcium metabolism.

•• Pathway <•> Klotho:

Klotho enhances the activity of TRPV5 by preventing its endocytosis and promoting its retention at the cell surface. This promotes an increase in calcium reabsorption, thus playing a vital role in maintaining calcium balance in the body.

••• Klotho <•> Pathway:

TRPV5 does not directly influence Klotho production or function. However, a proper calcium balance, mediated partly by TRPV5, is essential for various physiological processes, and disruptions might indirectly affect factors that influence Klotho.

•••• Downstream Pathways:

When TRPV5 is activated, it allows the entry of calcium into cells, which can activate several downstream pathways, including:

• Calmodulin-dependent protein kinase: Influences various cellular processes.

• Calcineurin signaling: Important for immune responses and other cellular processes.

• Calcium/Calmodulin-dependent protein kinase II (CaMKII): Has roles in memory and other neurological functions.

••••• Reciprocal Response:

Klotho influences the activity of TRPV5, but there isn't strong evidence suggesting that TRPV5 directly modulates Klotho levels in a feedback loop.

•••••• Diseases Associated with this Pathway:

• Hypercalciuria: Excessive calcium in urine, leading to kidney stone formation.

• Bone diseases: Altered calcium reabsorption can affect bone health, leading to conditions like osteoporosis.

• Nephrocalcinosis: Calcium accumulation in the kidneys.

••••••• Active Interventional Agents:

Several agents can modulate TRPV5 activity, including:

• Econazole: An inhibitor of TRPV5.

• Ruthenium red: Non-selective TRP channel blocker that can inhibit TRPV5.

• Klotho: As mentioned, Klotho can enhance the activity of TRPV5.

Understanding the interplay between Klotho and TRPV5 can provide insights into the regulation of calcium homeostasis, which is pivotal for bone health and preventing renal pathologies.

References:

[⬇︎][ TNF-α ][⬇︎]

Tumor Necrosis Factor-alpha (TNF-α)

This pathway Down-Regulates Klotho

Klotho Down-Regulates this Pathway

•(30)•

• Impact on Aging:

1. TNF-α is a pro-inflammatory cytokine involved in a myriad of cellular processes including inflammation, immune response, and apoptosis. Chronic inflammation is a hallmark of aging, and elevated levels of TNF-α have been linked to various age-related diseases such as rheumatoid arthritis, atherosclerosis, and Alzheimer's disease.

2. Klotho has anti-inflammatory properties, and its expression can reduce TNF-α production. Conversely, TNF-α can downregulate Klotho expression, further exacerbating inflammatory processes. Therefore, the interplay between Klotho and TNF-α can influence the pro-inflammatory state commonly seen in aging.

•• Pathway <•> Klotho:

TNF-α can lead to decreased expression of Klotho. This downregulation further augments the inflammatory state and might contribute to various pathologies, especially those associated with aging.

••• Klotho <•> Pathway:

Klotho has been shown to inhibit the actions of TNF-α, serving as an anti-inflammatory molecule. Thus, Klotho can potentially ameliorate the inflammatory effects of TNF-α.

•••• Downstream Pathways:

TNF-α activates several downstream pathways including:

• NF-κB pathway: A major inflammatory signaling pathway leading to the production of other inflammatory cytokines and mediators.

• MAPK pathway: Regulates cellular processes like proliferation, differentiation, and apoptosis.

• Apoptosis pathways: Through the activation of caspases leading to cell death.

••••• Reciprocal Response:

While TNF-α downregulates Klotho expression, it's unclear if Klotho directly modulates TNF-α levels in a feedback loop. However, by inhibiting TNF-α actions, Klotho can indirectly affect the levels of other inflammatory cytokines regulated by TNF-α.

•••••• Diseases Associated with this Pathway:

• Rheumatoid arthritis: An autoimmune disease with elevated TNF-α levels.

• Atherosclerosis: Chronic inflammation, partly driven by TNF-α, is a key component.

• Alzheimer's disease: Elevated TNF-α levels have been associated with the neuroinflammation seen in this disease.

• Inflammatory Bowel Diseases (IBD): Like Crohn’s disease, where TNF-α plays a significant role in its pathology.

••••••• Active Interventional Agents:

Several agents can modulate TNF-α activity, including:

• Infliximab, Adalimumab, Etanercept: Anti-TNF-α monoclonal antibodies used in treating diseases like rheumatoid arthritis.

• Thalidomide: Reduces TNF-α production.

• Klotho: As mentioned, it can inhibit TNF-α actions and might have therapeutic potential in conditions associated with elevated TNF-α levels.

Understanding the interaction between Klotho and TNF-α provides valuable insights into the role of inflammation in aging and age-associated diseases. Modulating this interaction might offer therapeutic opportunities.

References:

[2011] The Inflammatory Cytokines TWEAK and TNFα Reduce Renal Klotho Expression through NFκB

[⬇︎][ p53/p21 ][⬇︎]

Tumor Protein p53 and Cyclin-Dependent Kinase Inhibitor 1 (p53/p21)

This pathway Down-Regulates Klotho

Klotho Down-Regulates this Pathway

•(31)•

• Impact on Aging:

1. The p53/p21 pathway plays a pivotal role in regulating cell cycle, apoptosis, and DNA repair mechanisms. When cells experience DNA damage or other forms of stress, p53 is activated, leading to the induction of its target genes like p21, which halt cell cycle progression to allow DNA repair or induce apoptosis if the damage is irreparable. While this pathway acts as a tumor suppressor, preventing the propagation of damaged cells, its chronic activation can lead to senescence and is implicated in aging and age-related diseases.

2. There is evidence to suggest that Klotho can modulate the p53/p21 pathway. Reduced Klotho expression can lead to increased p53 and p21 expression, thus accelerating cellular senescence.

•• Pathway <•> Klotho:

The p53/p21 pathway, when chronically activated, can lead to the downregulation of Klotho expression, enhancing the aging phenotype and exacerbating age-related diseases.

••• Klotho <•> Pathway:

Klotho potentially downregulates the p53/p21 pathway. By inhibiting this pathway, Klotho can delay cellular senescence and extend cellular lifespan.

•••• Downstream Pathways:

Upon activation, p53 has several downstream effects:

• Induction of p21: This halts the cell cycle, providing time for DNA repair.

• Activation of pro-apoptotic genes like Bax and Noxa: Leading to programmed cell death if the damage is deemed irreparable.

• p53 also affects metabolic pathways, DNA repair mechanisms, and antioxidant defense systems.

••••• Reciprocal Response:

There is evidence to suggest that the p53/p21 pathway might downregulate Klotho expression, contributing to the aging phenotype. Conversely, Klotho has been shown to downregulate the p53/p21 pathway, delaying cellular senescence.

•••••• Diseases Associated with this Pathway:

• Cancer: Mutations in p53 are among the most common in cancers, affecting its role as a tumor suppressor.

• Cardiovascular Diseases: Cellular senescence, partly regulated by the p53/p21 pathway, has been linked to atherosclerosis and other cardiovascular conditions.

• Neurodegenerative Diseases: Implications in conditions like Alzheimer’s due to roles in cellular survival and death.

••••••• Active Interventional Agents:

Several agents target the p53/p21 pathway, including:

• Nutlin-3: Disrupts the interaction between p53 and its negative regulator MDM2, stabilizing p53.

• PRIMA-1 and PRIMA-1^MET (PRIMA-1^MET is also known as APR-246): Reactivate mutant p53 to its wild-type conformation.

• Klotho: As previously mentioned, it might act to inhibit the p53/p21 pathway, delaying cellular senescence.

Understanding the interaction between Klotho and the p53/p21 pathway can provide valuable insights into cellular senescence, aging, and age-associated diseases, offering potential therapeutic interventions.

References:

[⬆︎][ VDRE ][⬆︎][₪]

Vitamin D Receptor Element (VDRE)

Unknown if this pathway modulates Klotho

Klotho Up-Regulates this Pathway

•(32)•

• Impact on Aging:

1. The VDRE pathway primarily deals with the genomic effects of the active vitamin D hormone, calcitriol (1,25-dihydroxyvitamin D3). The binding of calcitriol to its receptor, VDR (Vitamin D Receptor), allows it to bind to VDRE in the genome, affecting the expression of various genes. These genes play roles in calcium homeostasis, cell proliferation, differentiation, apoptosis, and immune response. A decline in vitamin D and its signaling might be associated with several age-related diseases and conditions, including osteoporosis, muscle weakness, and certain types of cancer.

2. Klotho plays a role in the synthesis of active vitamin D. It acts as a co-receptor for FGF23, a hormone that downregulates the production of 1,25-dihydroxyvitamin D3 in the kidneys. Reduced Klotho levels can lead to altered vitamin D metabolism, with potential impacts on aging and related pathologies.

3. Klotho has been described as an aging suppressor, and alterations in Vitamin D metabolism, regulated in part by Klotho, are implicated in aging and age-related diseases. Thus, Klotho's interactions with the Vitamin D pathway may play a crucial role in the physiology of aging.

4. The Klotho protein is known for its anti-aging properties. The interaction of Klotho with the VDRE pathway to maintain mineral ion homeostasis contributes to this anti-aging effect. Dysregulation of this pathway may accelerate aging and age-related disorders, particularly those affecting the kidneys and skeletal system.

•• Pathway <•> Klotho:

The VDRE pathway's activity can be influenced by Klotho, particularly through its role in FGF23 signaling which affects active vitamin D synthesis. Reduced Klotho might lead to decreased vitamin D activation, thus influencing the genomic effects mediated by the VDRE pathway.

••• Klotho <•> Pathway:

Klotho downregulates the VDRE pathway, especially through its interaction with FGF23, which subsequently affects the production of active vitamin D in the kidneys.

•••• Downstream Pathways:

Upon activation, the VDRE pathway can influence:

• Calcium homeostasis through genes regulating intestinal calcium absorption, renal calcium reabsorption, and bone remodeling.

• Cell cycle progression, affecting genes responsible for cell proliferation, differentiation, and apoptosis.

• Immune response genes, modulating inflammation and immunity.

••••• Reciprocal Response:

Vitamin D engages with multiple mechanisms to potentially activate the Klotho gene and influence Klotho protein activity. It can upregulate Klotho gene expression directly by binding to Vitamin D Receptors (VDRs) that then interact with Vitamin D Response Elements (VDREs) in the Klotho gene. Furthermore, Vitamin D also modulates peripheral pathways related to Klotho activity. It upregulates the Fibroblast Growth Factor 23 (FGF23) pathway, which is closely related to Klotho function. There might be synergistic opportunities within the interaction between Vitamin D and the FGF23 pathway, potentially enhancing Klotho activity. [2].

Upregulation of the VDRE pathway by Klotho leads to the activation of vitamin D-responsive genes, which control mineral ion homeostasis and bone metabolism. Furthermore, vitamin D signaling may also influence cell growth, differentiation, and immune responses. Klotho expression is up-regulated by 1,25-(OH)2 D, suggesting that klotho participates in a vitamin D feedback loop. [1] The anti-aging effect of vitamin D is also involved in AD, by increasing the expression of an anti-aging gene Klotho, as well as decreasing the expression and inhibiting the activity of aging-related protein mTOR, through PI3K/Akt/mTOR pathway [4].

•••••• Diseases Associated with this Pathway:

• Osteoporosis: Reduced vitamin D signaling affects bone mineral density.

• Cancers: Especially breast, prostate, and colon cancers.

• Autoimmune diseases: Like multiple sclerosis and type 1 diabetes.

• Muscle weakness and frailty.

••••••• Active Interventional Agents:

Several agents can influence the VDRE pathway, such as:

• Calcitriol and analogs: Direct activators of the VDR.

• Vitamin D3 (cholecalciferol) and Vitamin D2 (ergocalciferol): Precursors that are converted to active vitamin D in the body.

• Paricalcitol and Doxercalciferol: Synthetic VDR activators.

• Klotho: As previously mentioned, its involvement with FGF23 signaling impacts active vitamin D synthesis.

Curcumin, Vitamin D

We carried out real time PCR utilizing RNA isolated from mouse (IMCD-3 and mpkDCT) cells as described previously [42] with primers designed to capture both alternatively spliced mRNAs for the membrane and secreted forms of klotho. The results (Fig. 6a) indicate that 1,25D treatment (100 nM for 24 hours) induces klotho mRNA expression in the mouse distal tubule cell line (mpkDCT) as well as in the inner medullary collecting duct cells (IMCD-3). This induction is evident for both the membrane and secreted forms of klotho mRNA, suggesting that 1,25D may be capable of both amplifying FGF responsiveness and eliciting secretion of circulating klotho hormone. These data complement our previous demonstration of klotho mRNA induction by 1,25D in human proximal kidney (HK-2) cells [10]. Interestingly, curcumin, an alternative VDR ligand [43], selectively upregulates membrane klotho mRNA in mpkDCT cells, indicating that distinct VDR ligands can differentially modulate the membrane and secreted forms of klotho. These data lead to the hypothesis that designer vitamin D analogs could promote the healthful aging benefits of systemic klotho without accentuating FGF23 action to perhaps elicit hypophosphatemia.

[2012] The Role of Vitamin D in the FGF23, Klotho, and Phosphate Bone-Kidney Endocrine Axis

References:

[1] [2003] Klotho, a Gene Related to a Syndrome Resembling Human Premature Aging, Functions in a Negative Regulatory Circuit of Vitamin D Endocrine System.pdf

[2] [2011] Vitamin D receptor controls expression of the anti-aging klotho gene in mouse and human renal cells.pdf

[3] [2012] The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis

[4] [2023] Vitamin D and neurodegenerative diseases

[⬇︎][ Wnt ][⬇︎]

Wingless/Integrated Signaling Pathway (Wnt)

This Pathway Down-Regulates Klotho

Klotho Down-Regulates this Pathway

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• Impact on Aging:

1. The Wnt signaling pathway is crucial for various cellular processes, including cell proliferation, differentiation, migration, and stem cell maintenance. Dysregulation of the Wnt pathway has been linked to numerous age-associated conditions, including cancer, osteoporosis, and neurodegenerative diseases.

2. Klotho is known to act as a secreted Wnt antagonist. Soluble Klotho can bind to various Wnt ligands, inhibiting Wnt signaling. This interaction between Klotho and Wnt might provide protective effects against age-associated conditions.

•• Pathway <•> Klotho:

The Wnt pathway can be down-regulated by Klotho. Soluble Klotho inhibits Wnt signaling by binding directly to Wnt ligands, thereby suppressing the activation of the Wnt pathway and its downstream effects.

••• Klotho <•> Pathway:

The Wnt pathway can down-regulate Klotho. Some studies suggest that increased Wnt signaling can decrease Klotho expression, indicating a reciprocal regulatory relationship between the two.

•••• Downstream Pathways: Upon activation, the Wnt pathway can lead to:

• β-catenin stabilization and translocation into the nucleus, affecting gene transcription.

• Activation of Planar Cell Polarity and Wnt/Ca^2+ pathways, influencing cell adhesion and movement.

• Influence on stem cell niche maintenance and organ regeneration.

••••• Reciprocal Response:

There is evidence of a reciprocal relationship between Klotho and the Wnt pathway. As Klotho suppresses Wnt signaling, heightened Wnt signaling can lead to the down-regulation of Klotho expression.

•••••• Diseases Associated with this Pathway:

• Cancer: Overactive Wnt signaling is associated with various cancers, including colorectal cancer.

• Osteoporosis: Altered Wnt signaling affects bone formation and remodeling.

• Neurodegenerative diseases: Dysregulation of the Wnt pathway is seen in conditions like Alzheimer's disease.

• Chronic kidney disease: Reduced Klotho and altered Wnt signaling play roles in kidney pathology.

••••••• Active Interventional Agents: Several agents can influence the Wnt pathway:

• Dkk1: An inhibitor of the Wnt pathway.

• LRP5/6 antagonists: These inhibit Wnt signaling by preventing Wnt ligand-receptor interactions.

• Tankyrase inhibitors: These can stabilize axin and promote β-catenin degradation, suppressing Wnt signaling.

• Klotho: As an antagonist, it binds to Wnt ligands, suppressing Wnt signaling.

• Wnt Receptors (LRP5/LRP6): The soluble form of Klotho can bind to the Wnt co-receptors LRP5 and LRP6, thereby inhibiting Wnt signaling. This mechanism is involved in the regulation of cell proliferation and differentiation and plays a role in various diseases and aging.

The Wnt signaling pathway and its interaction with Klotho offer potential therapeutic avenues for various age-associated conditions. Targeting this interplay could pave the way for innovative treatments in the realm of regenerative medicine and anti-aging therapies.

References: