Combinatorial Goals:

Each Active Agent on this page has demonstrated an ability to: 1) [DA] directly activate Klotho; 2) [SI] Increase systemic levels of Klotho; 3) [MP] Up-Regulate upstream Molecular Pathways known to increase systemic levels of Klotho; 4) [DM] Remove meythalation marks on the promoter reagon of Klotho DNA; 5) [AO] dramatically increase the antioxidants; 6) [SE] Increase the signaling potential of the signaling environment.

List is Alphabetized, not ranked by scores or strength of Klotho Increasing Potential.

In clinical practice the goals of combination drug treatment are to obtain a synergistic therapeutic effect, to reduce the dose, to minimize toxicity, to achieve a rapid onset of action, and to insure a long-lasting therapeutic effect.  

A high-level overview of each Active-Agent with the potential for Klotho regulation is provided in alphabetical order below. These profiles produce a high level overview, that can be utilized to stratify active agents.

The Molecular Pathways and Synergistic Agent interactions are a different ChatGPT prompt than was utilized to generate the entries shown below.

Klotho Regulation Keys

ACE Inhibitors

1) Biological / Pharmacological / Pharmacokinetics Profile

ACE Inhibitors (Angiotensin-Converting Enzyme Inhibitors) are a class of medications used to treat conditions like hypertension, heart failure, and chronic kidney disease. They function by inhibiting the conversion of angiotensin I to angiotensin II, reducing vasoconstriction, and aldosterone secretion, leading to decreased blood pressure and workload on the heart. Pharmacokinetically, ACE inhibitors show variable absorption with oral administration, and their elimination occurs primarily through renal excretion. The bioavailability and half-life differ between individual ACE inhibitors.

2) Molecular Pathways ACE inhibitors modulate the following pathways:

• Angiotensin-Converting Enzyme 2 (ACE2): Direct inhibition.

• Renin-Angiotensin System (RAS): Down-regulation through inhibition of angiotensin II formation.

3) Impact on Klotho

ACE inhibitors may indirectly up-regulate Klotho by modulating the RAS pathway, positively affecting the cardiovascular system, kidneys, and overall aging process.

4) Safety Profile

ACE inhibitors are generally well-tolerated but can have side effects like cough, increased blood potassium levels, low blood pressure, kidney dysfunction, and elevated blood urea nitrogen (BUN) and serum creatinine. Monitoring of kidney function is essential.

5) Oral Bioavailability

Oral bioavailability varies among different ACE inhibitors. For example, Lisinopril has a bioavailability of around 25%, while Ramipril has a bioavailability of 50-60%.

6) Plasma Half-Life

The plasma half-life of ACE inhibitors differs among the various drugs. Enalapril has a half-life of around 11 hours, while Lisinopril's half-life is around 12 hours.

7) Additive, Complementary, or Synergistic

ACE inhibitors may have additive effects with other antihypertensive medications and synergistic effects with diuretics.

8) Antagonistic

ACE inhibitors may have antagonistic effects with nonsteroidal anti-inflammatory drugs (NSAIDs), leading to a decrease in antihypertensive effectiveness.

9) Diseases Impacted by Active Agent

ACE inhibitors are used to treat:

• Hypertension

• Heart Failure

• Chronic Kidney Disease

• Post Myocardial Infarction

10) Human Clinical Trials of Active Agent

Numerous clinical trials have investigated ACE inhibitors in cardiovascular diseases. Studies like the HOPE and SOLVD trials have demonstrated significant benefits in heart failure and post-MI patients.

11) Known Anti-Aging Effects Attributable to Active-Agent

The anti-aging effects of ACE inhibitors may be indirectly related to their beneficial impact on cardiovascular health, renal protection, and potential modulation of Klotho. By inhibiting angiotensin II, they may contribute to vascular health, reduce inflammation, and enhance cellular repair processes, although further research is required to elucidate specific anti-aging mechanisms.

12) References

[2013] ACE Inhibition with Captopril Retards the Development of Signs of Neurodegeneration in an Animal Model of Alzheimer’s Disease

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

[2022] Calpain Inhibitor Calpeptin Alleviates Ischemia/Reperfusion-Induced Acute Kidney Injury via Suppressing AIM2 Inflammasome and Upregulating Klotho Protein

Activated Charcoal

Biological / Pharmacological / Pharmacokinetics Profile

Activated charcoal, or activated carbon, is a form of carbon that has been processed to create a large surface area of micro-pores, enabling a significant increase in adsorption capacity. It is commonly used to treat poisoning and drug overdose, as it can adsorb a variety of chemicals, reducing their systemic absorption. It's important to note that the effectiveness of activated charcoal depends on the specific chemical involved and the time elapsed since ingestion.

Molecular Pathways

Activated charcoal does not act by modulating specific molecular pathways but instead operates through physical adsorption of molecules, including toxins, drugs, and chemicals. Its mechanism of action is non-specific, and it is not known to target the specific pathways listed in the overview.

Impact on Klotho

There is currently no evidence to suggest that activated charcoal directly or indirectly upregulates Klotho. Its action is not related to specific molecular signaling or cellular regulation but rather to the physical trapping of substances.

Safety Profile

Activated charcoal is considered generally safe when administered properly. Common side effects can include black stools, vomiting, diarrhea, or constipation. Inhalation of activated charcoal dust can lead to respiratory issues. It may also reduce the absorption of certain nutrients and medications if taken concurrently.

Oral Bioavailability

As a non-systemic agent, activated charcoal is not absorbed into the blood. Its bioavailability is not relevant as it works within the gastrointestinal tract.

Plasma Half-Life

Activated charcoal does not have a plasma half-life as it is not absorbed into the systemic circulation.

Additive, Complementary, or Synergistic

Activated charcoal does not have known synergistic effects with other medications or compounds in terms of enhancing therapeutic effects. It can be used with other treatments for poisoning, such as antidotes specific to the toxin involved, to provide supportive care.

Antagonistic

Activated charcoal may interfere with the absorption of various drugs and nutrients if administered concomitantly, acting as an antagonist to their effect.

Diseases Impacted by Active Agent

Activated charcoal is used to treat acute poisoning and overdoses of various substances, including many pharmaceutical drugs and household chemicals.

Human Clinical Trials of Active Agent

Numerous trials have investigated the efficacy of activated charcoal in treating poisonings and overdoses, including its use in emergency settings.

Known Anti-Aging Effects

Attributable to Active-Agent Activated charcoal does not have known direct anti-aging effects. Its main use is in the adsorption of toxins, and it is not associated with the modulation of molecular pathways that impact aging.

References

[2010] An Oral Sorbent, AST-120, Increases Klotho Expression and Inhibits Cell Senescence in the Kidney of Uremic Rats

[2012] Chronic Kidney Disease-Induced Cardiac Fibrosis Is Ameliorated by Reducing Circulating Levels of a Non- Dialysable Uremic Toxin, Indoxyl Sulfate

[2012] Identification of novel small molecules that elevate Klotho expression

Adenosine

Adiponectin

Akkermansia muciniphila

Alpha-Ketoglutaric Acid Ornithine (AKG)

◉Alpha-Lopic Acid

1) Biological / Pharmacological / Pharmacokinetics Profile

Alpha-Lipoic Acid (ALA) is a naturally occurring compound that plays a crucial role in energy metabolism. It's recognized as an essential cofactor for several mitochondrial enzyme complexes, facilitating the production of ATP.

• Biological Function: ALA is a potent antioxidant that is both water and fat-soluble. It can regenerate other antioxidants like vitamins C and E, coenzyme Q10, and glutathione. ALA also influences insulin signaling pathways and may improve glucose utilization.

• Pharmacology: ALA acts as a cofactor for multiple enzyme complexes involved in mitochondrial energy metabolism. Its antioxidant properties provide neuroprotection and may help in peripheral neuropathy.

• Pharmacokinetics: ALA has a rapid absorption rate and is widely distributed throughout the body. Its bioavailability is around 30%, and its plasma half-life is approximately 30 minutes to 1 hour. It is metabolized in the liver and excreted in the urine.

2) Molecular Pathways

ALA modulates several molecular pathways:

• Antioxidant Pathways: Upregulates Nrf2, promoting antioxidant responses.

• Anti-inflammatory Pathways: Inhibits NF-κB, reducing inflammation.

• Glucose Metabolism: Influences Insulin Signaling Pathway (ISP), enhancing insulin sensitivity.

• Energy Regulation: Impacts Adenosine Monophosphate-Activated Protein Kinase (AMPK), promoting energy homeostasis.

3) Impact on Klotho

There is no direct evidence to suggest that ALA up-regulates Klotho. However, its positive impact on insulin sensitivity and antioxidative stress mechanisms could indirectly support pathways that are favorable to Klotho expression.

4) Safety Profile

ALA is generally well-tolerated. Common side effects may include nausea, stomach upset, and skin rash. Some precautions are needed for those with diabetes, as ALA might lower blood sugar levels.

5) Oral Bioavailability

The oral bioavailability of ALA is around 30%.

6) Plasma Half-Life

The plasma half-life of ALA is approximately 30 minutes to 1 hour.

7) Additive, Complementary, or Synergistic

ALA can be synergistic with other antioxidants such as vitamin C and E, enhancing their effects.

8) Antagonistic

No known antagonistic effects with the other active agents identified in the overview.

9) Diseases Impacted by Active Agent

ALA has demonstrated therapeutic benefits in:

• Diabetic Peripheral Neuropathy

• Alzheimer's Disease

• Glaucoma

• Cardiovascular Diseases

10) Human Clinical Trials of Active Agent

Several clinical trials have investigated ALA's effects on diabetic neuropathy, metabolic syndrome, and cognitive function in Alzheimer's disease.

11) Known Anti-Aging Effects Attributable to Active-Agent

ALA's antioxidant, anti-inflammatory properties, and impact on glucose metabolism could contribute to anti-aging effects by:

• Reducing oxidative stress

• Improving mitochondrial function

• Enhancing insulin sensitivity

These effects could collectively slow down the aging process by maintaining cellular function and integrity.

ApigeninAST-120

Astaxanthin

Astragaloside

Astragalus Membranaceus

Atrasentan

Baicalein

Berberine

Bufei Yishen Formula

Calorie Restriction

Carnitine

Carnitine functions as an enhancer of NRF2 to inhibit osteoclastogenesis via regulating macrophage polarization in osteoporosis.

Mechanistically, carnitine enhanced the function of Nrf2 by inhibiting the Keap1-Nrf2 interaction, reducing the proteasome-dependent ubiquitination and degradation of Nrf2. In silico molecular ligand docking analysis of the interaction between carnitine and Keap1 showed that carnitine binds to Keap1 to stabilize Nrf2 and enhance its function. Prior studies have demonstrated increases in Klotho levels by up regulating Nrf2.

• [2024] Carnitine functions as an enhancer of NRF2 to inhibit osteoclastogenesis via regulating macrophage polarization in osteoporosis

Chlorgenic acid

Nrf2 <•> NfKb CGA is capable of inducing Nrf2 signaling [85,86]. CGA (10 mg/kg daily for 8 weeks) alleviate DN via affecting Nrf2 signaling. CGA stimulates Nrf2 signaling to increase the level of HO-1, and to reduce NF-ĸB expression, resulting in decreased inflammation and oxidative stress in DN. Of note, an interaction is noted between Nrf2 and NF-ĸB in DN. Silencing Nrf2 signaling promotes nuclear translocation of NF-ĸB and increases generation of cytokines. On the other hand, nuclear translocation of Nrf2 and expression level of HO-1 increase after NF-ĸB inhibition, confirming an inverse relationship between Nrf2 and NF-ĸB in DN [89].

• N. Yun, J.-W. Kang, S.-M.J.T.J.o.N.B. Lee, in: Protective effects of chlorogenic acid against ischemia/reperfusion injury in rat liver: molecular evidence of its antioxidant and anti-inflammatory properties 23(10), 2012, pp. 1249–1255.

• ] R. Jiang, et al., in: Chlorogenic acid improves ex vivo vessel function and protects endothelial cells against HOCl-induced oxidative damage, via increased production of nitric oxide and induction of Hmox-1 27, 2016, pp. 53–60.

• 9] L. Bao, et al., Chlorogenic acid prevents diabetic nephropathy by inhibiting oxidative stress and inflammation through modulation of the Nrf2/HO-1 and NFĸB pathways, Int. Immunopharmacol. 54 (2018) 245–253.

ChrysinCordycepin

Curcumin

◉ [DA] [AO] [MP] [₪]

1) Curcumin [15, 102]: Curcumin is a natural compound found in turmeric, it has been shown to up-regulate Klotho Expression Directly. Curcumin demonstrates a secondary Klotho up-regulation component, potent Antioxidant and anti-inflammatory properties. Curcumin can also elicit DNA demethylation. Curcumin binds the VDR element resulting in an increase in Klotho levels. Curcumin has been shown to activate the Nrf2 pathway, leading to the expression of various antioxidant and cytoprotective genes.  Curcumin also down regulates TNF-α, resulting in an increase in Klotho levels. Oral bioavailability is low and can be increased by the addition of peperine and by lyphoization and/or micronization.  Curcumin is generally regarded as safe (GRAS). 

[2017] A Novel Highly Bioavailable Curcumin Formulation Improves Symptoms and Diagnostic Indicators in Rheumatoid Arthritis Patients:
A Randomized, Double-Blind, Placebo-Controlled, Two-Dose, Three-Arm, and Parallel-Group Study

[2018] Upregulation of klotho and erythropoietin contributes to the neuroprotection induced by curcumin-loaded nanoparticles in experimental model of chronic epilepsy

[2016] Curcumin attenuates cyclosporine A‑induced renal fibrosis by inhibiting hypermethylation of the klotho promoter

[2021] Epigenetic and non-epigenetic regulation of Klotho in kidney disease

1) Biological / Pharmacological / Pharmacokinetics Profile

• Curcumin is a natural polyphenolic compound extracted from the spice turmeric (Curcuma longa). It boasts an extensive range of pharmacological activities: anti-inflammatory, antioxidant, anti-tumor, antiviral, antibacterial, and antifungal actions. However, it has limitations like poor solubility, rapid metabolism, and swift systemic elimination.

2) Molecular Pathways

• Curcumin has an impact on multiple cellular pathways, including:

  • KL

  • NF-κB

  • AKT

  • MAPK

  • p53

  • Nrf2

    • [2014] Screening of Natural Compounds as Activators of the Keap1- Nrf2 Pathway.pdf alias

    • [2022] Nrf2 Regulation by Curcumin- Molecular Aspects for Therapeutic Prospects

    • [2022] Nrf2-Related Therapeutic Effects of Curcumin in Different Disorders

  • COX-2

  • VDRE

    • [2010] Curcumin- a novel nutritionally derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention

  • Epigenetics

    • [2011] Epigenetic changes induced by curcumin and other natural compounds

3) Impact on Klotho

• According to the data up to September 2021, the direct connection between curcumin and Klotho upregulation is not solidly established. There's some evidence suggesting curcumin might modulate Klotho, especially in contexts like kidney disease and neuroprotection. Nevertheless, this link demands further investigation.

4) Safety Profile

• Generally safe when taken in moderate dietary amounts, curcumin at higher doses (often above 8g daily) might lead to gastrointestinal distress, diarrhea, headaches, rashes, and yellow stools. It could also interfere with anticoagulant and antiplatelet medications, thus enhancing bleeding risk.

5) Oral Bioavailability

• Curcumin's oral bioavailability is notably poor. This is a result of its poor solubility, swift metabolism, and quick systemic removal. Efforts to enhance its bioavailability have involved formulations with nanoparticles, liposomes, and agents like piperine. An improved formulation is proposed by the manufactures of CuraMed Curcumin.

  • [2017] A Novel Highly Bioavailable Curcumin Formulation Improves Symptoms and Diagnostic Indicators in Rheumatoid Arthritis Patients- A Randomized, Double-Blind, Placebo-Controlled, Two-Dose, Three-Arm, and Parallel-Group Study

  • [2021] THE PHARMACOLOGICAL BASIS OF THE CURCUMIN NUTRACEUTICAL USES- AN UPDATE

6) Plasma Half-Life

• The plasma half-life of curcumin lies between approximately 2.5 to 4.5 hours.

7) Additive, Complementary, or Synergistic

• Several agents have been identified to be complementary with curcumin:

  • [2019] Exploiting Curcumin Synergy With Natural Products Using Quantitative Analysis of Dose–Effect Relationships in an Experimental In Vitro Model of Osteoarthritis

    • Piperine: Increases bioavailability by hindering curcumin metabolism.

    • Omega-3 fatty acids: Potentially amplify curcumin's anti-inflammatory properties.

    • Quercetin and green tea polyphenols: These may operate synergistically with curcumin in select anti-cancer and anti-inflammatory pathways.

    • Beta-caryophyllene

      • [2022] Beta-caryophyllene prevents the defects in trabecular bone caused by Vitamin D deficiency through pathways instated by increased expression of klotho

8) Diseases Impacted by Curcumin

• Curcumin has shown potential therapeutic effects in:

  • Direct Up-Regulation of Klotho

  • Inflammatory disorders (e.g., osteoarthritis, rheumatoid arthritis)

  • Metabolic syndromes and related conditions such as diabetes

  • Neurological conditions (e.g., Alzheimer's, depression)

  • Various forms of cancer (e.g., colon, breast, prostate)

  • Gastrointestinal issues, particularly inflammatory bowel disease

9) Human Clinical Trials of Curcumin

• A large number of human clinical trials have studied curcumin for a myriad of conditions. For a comprehensive list and detailed outcomes, one should consult clinical trial databases such as ClinicalTrials.gov.

10) Known Anti-Aging Effects Attributable to Curcumin

• Curcumin holds antioxidant properties that neutralize free radicals, mitigating oxidative stress, a prominent factor in aging. It enhances the Nrf2 pathway, leading to the upregulation of antioxidant enzymes and cytoprotective proteins. Additionally, it modulates inflammation, linked with many age-related ailments. It also offers potential defense against age-related cognitive decline by curbing neuroinflammation and amyloid-beta accumulation.

11) References:

[2010] The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis

[2011] Epigenetic changes induced by curcumin and other natural compounds.pdf alias

[2018] Upregulation of klotho and erythropoietin contributes to the neuroprotection induced by curcumin-loaded nanoparticles in experimental model of chronic epilepsy

[2020] Curcumin-Induced DNA Demethylation in Human Gastric Cancer Cells Is Mediated by the DNA-Damage Response Pathway.pdf alias

[2021] The Pharmacological Basis of The Curcumin Nutraceutical Uses - An Update

[2019] Exploiting Curcumin Synergy With Natural Products Using Quantitative Analysis of Dose–Effect Relationships in an Experimental In Vitro Model of Osteoarthritis

[2023] Anti-Inflammatory Klotho Protein Serum Concentration Correlates with Interferon Gamma Expression Related to the Cellular Activity of Both NKT-like and T Cells in the Process of Human Aging

[2023] Dietary Curcumin Attenuates Hepatic Cellular Senescence by Suppressing the MAPK/NF-κB Signaling Pathway in Aged Mice

Quaniol

Diet

Diosmetin

Ellagic Acid

Epicatechin gallate (ECG)

Epigallocatechin gallate

Eplerenone (SARA) blood pressure

Everolimus

Exercise

In both humans and mice. Klotho only increases post-exercise in people who completed a 16-week training program, with younger people having a bigger increase than older people. Based on mouse studies, it’s believed that muscle injury and new muscle cells secrete Klotho.

Fasting

Fisetin

Fluoride

Fluvastatin

Fu-TiGABA

Galangin

Genistein

Ginkgo Biloba

ginsenoside Rg1GLP-1-based Gotu Kola

Green Tea Polyphenlys (GTP) EGCG

1) Biological / Pharmacological / Pharmacokinetics Profile

Epigallocatechin gallate (EGCG) is a polyphenol present in green tea, having potent antioxidant, anti-inflammatory, and anticarcinogenic properties. It has been found to have a wide range of therapeutic applications in various diseases.

Pharmacodynamics: EGCG exerts its effects through various mechanisms such as inhibiting certain enzymes like tyrosine kinase, modulating cell signaling pathways, chelating metal ions, scavenging free radicals, and interacting with cell membrane proteins and lipids.

Pharmacokinetics:

• Absorption: EGCG is absorbed in the small intestine but in limited amounts.

• Distribution: Distributed throughout the body, with notable concentrations in the liver.

• Metabolism: Extensively metabolized in the liver by methylation, glucuronidation, and sulfation.

• Elimination: Eliminated via both urine and feces.

2) Molecular Pathways

EGCG modulates several molecular pathways:

• Upregulates Nrf2, AMPK, and SIRT1 pathways.

• Downregulates NF-κB, MAPK, mTOR, and Wnt signaling pathways.

• Modulates PI3K/Akt pathway, which plays a significant role in cellular survival and growth.

3) Impact on Klotho

Current literature does not provide concrete evidence of EGCG directly or indirectly up-regulating Klotho. Further studies may be required to determine any potential connection.

4) Safety Profile

EGCG is generally considered safe when consumed within the daily intake of green tea. However, high doses of EGCG supplements can lead to liver toxicity, gastrointestinal discomfort, and anemia.

5) Oral Bioavailability

The oral bioavailability of EGCG is relatively low, ranging from 0.1% to 1.7%. This low bioavailability is due to extensive metabolism, poor stability in neutral and alkaline conditions, and low permeability across the intestinal wall.

6) Plasma Half-Life

The half-life of EGCG in human plasma is approximately 2 to 3.4 hours.

7) Additive, Complementary, or Synergistic

EGCG has been found to have synergistic effects with agents such as:

• Curcumin

• Resveratrol

• Quercetin

8) Antagonistic

No known antagonistic effects with other active agents identified in the overview have been reported.

9) Diseases Impacted by Active Agent

EGCG has demonstrated therapeutic activity in:

• Cancer

• Cardiovascular diseases

• Neurodegenerative diseases (Alzheimer’s, Parkinson’s)

• Diabetes

• Liver diseases

10) Human Clinical Trials of Active Agent

Numerous human clinical trials have been conducted to evaluate EGCG's effects, especially in the areas of cancer prevention, weight management, cardiovascular health, and cognitive function.

11) Known Anti-Aging Effects Attributable to Active-Agent

EGCG contributes to anti-aging through:

• Antioxidant properties, reducing oxidative stress

• Anti-inflammatory effects

• Enhancing metabolic regulation

• Potential neuroprotective effects

12) References

Guanosine (ginsenoside Rg1)

Haikun Shenxi (Chinese approved Drug)

Hesperidin

Hibiscus sabdariffa

Hyaluronic AcidI-Histidine

Intermedin Ketone

L-carnitine tartrate

L-CystineL-Isoleucine (bcaa)

L-Leucine (bcaa)

L-LysineL-Methionine

L-PhenylalanineL-serine

L-serine

L-theanine ++ memory in Klotho -/- mice

L-Threonine

L-TriptophanL-Tyrosine

L-Valine (bcaa)

Latanoprost

Ligustilide (Dong Quai)

Lipitor

Lithium

Losartan

Losartan (Angiotensin II Receptor Blocker (ARB))

Luteolin

Magnesium

Manganese

Meditation

Melatonin

Metadichol, Policosanol

Metformin

1) Biological / Pharmacological / Pharmacokinetics Profile

Metformin is a biguanide class of antidiabetic medications that's commonly used to treat type 2 diabetes. It works by decreasing hepatic glucose production, decreasing the intestinal absorption of glucose, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin also exerts pleiotropic effects on cellular metabolism, energy balance, and may have effects that are relevant to aging and age-related diseases. Metformin is an insulin sensitizer that activates AMPK. Metformin produces anti-ageing effect by remodelling the energy distribution, increasing glutathione levels (antioxidant), and mimicking diet restriction via activation AMPK-p53-FOXO pathway.

2) Molecular Pathways

Metformin modulates various molecular pathways including:

• Adenosine Monophosphate-Activated Protein Kinase (AMPK): Activation leading to increased catabolic pathways.

• mTOR pathway: Inhibition, related to cellular growth and proliferation.

• Insulin Signaling Pathway (ISP): Enhancement, improving insulin sensitivity.

• Nuclear factor-kappa Beta (NF-κB) pathway: Potential inhibition, affecting inflammation.

3) Impact on Klotho

There are limited studies directly connecting Metformin and Klotho expression. However, by positively modulating pathways such as AMPK that are known to upregulate Klotho, Metformin may indirectly contribute to Klotho regulation.

4) Safety Profile

Metformin is generally well-tolerated but may cause gastrointestinal side effects, such as diarrhea and abdominal pain. Rarely, it can lead to vitamin B12 deficiency and lactic acidosis, particularly in those with renal impairment.

5) Oral Bioavailability

The oral bioavailability of Metformin is approximately 50-60%.

6) Plasma Half-Life

Metformin's plasma half-life is about 5-6 hours.

7) Additive, Complementary, or Synergistic

Metformin has synergistic effects with other antidiabetic drugs such as sulfonylureas and thiazolidinediones.

8) Antagonistic

No widely recognized antagonistic effects with the other active agents identified in the overview.

9) Diseases Impacted by Active Agent

Metformin is used primarily in type 2 diabetes but has also shown potential in polycystic ovary syndrome (PCOS), metabolic syndrome, and as an adjunctive treatment in cancer.

10) Human Clinical Trials of Active Agent

Numerous clinical trials have investigated Metformin in diabetes, and several ongoing trials are examining its potential in aging, cancer prevention, cardiovascular disease, and other age-related conditions.

11) Known Anti-Aging Effects Attributable to Active-Agent

Metformin has been proposed as a geroprotective agent with potential anti-aging effects. The activation of AMPK, inhibition of mTOR, and effects on cellular metabolism may contribute to its anti-aging properties. Several clinical trials are aimed at exploring this potential further.

12) References

[2016] Effects of Metformin on Serum Levels of Secreted Klotho and Leptin in PCOS Women

miR-199b-5p |

miRNA130am

miRNA152/30m

miRNA339m

miRNA34am

miRNA556

Morin

N-acetyl-L-cysteine (NAC)

NAD3

Neferine

[2019] Neferine attenuates acute kidney injury by inhibiting NF-kappaB signaling and upregulating klotho expression.

Nicotinamide mononucleotide (NMN) (Vit B3)

Nicotinamide riboside

Nicotinamide riboside (NR) (Vit B3)

Nobiletin

Oleuropein, (Olive polyphenols)

ParishinPentoxifylline (PTXF)

Probiotics

Acidophilus + L Lactis in aging mice [30].

Pterostilbene

Qing'E

Quercetin

Rapamycin

Red Ginseng

Resveratrol (astragalus triphenol)

2) [₪]  Resveratrol [14, 102] : This compound, found in red wine and grapes, can upregulate Klotho Expression Directly. Resveratrol and Curcumin produce a synergistic result because both compounds are known to activate the SIRT1, Nrf2, and PPARγ pathways, and both also have DNA demethylating activity that directly influence Klotho expression. Resveratrol is a potent Antioxidant. Each of these pathways are known to be signaling activators of Klotho.

[₪] [2019] Resveratrol and 1,25-dihydroxyvitamin D co-administration protects the heart against d-galactose-induced aging in rats- evaluation of serum and cardiac levels of klotho

[2014] Resveratrol increases anti-aging Klotho gene expression via the activating transcription factor 3/c-Jun complex-mediated signaling pathway

[2021] Resveratrol (RV)- A pharmacological review and call for further research. (Image Source)

Rhein >>> Da Huang (Rubarb)

RNA, miRNA SiRNA, piRNA

Rosiglitazone

Rosmarinic acid (RA)

1) Biological / Pharmacological / Pharmacokinetics Profile

Rosmarinic Acid is a polyphenolic compound with known antioxidant, anti-inflammatory, antimicrobial, and neuroprotective properties.

Pharmacodynamics:

• Antioxidant Action: RA scavenges free radicals and inhibits lipid peroxidation.

• Anti-inflammatory Effect: Modulates inflammatory pathways by inhibiting pro-inflammatory cytokines.

• Neuroprotective Effect: RA has shown neuroprotective effects in models of neurological disorders.

Pharmacokinetics:

• Absorption: Rapidly absorbed in the gastrointestinal tract.

• Distribution: Distributed to tissues including the liver and brain.

• Metabolism: Metabolized mainly in the liver by glucuronidation and sulfation.

• Elimination: Excreted in the urine and feces.

2) Molecular Pathways

RA exerts its effects through various pathways:

• Inhibition of NF-κB Pathway: Reducing inflammation and oxidative stress.

• Activation of Nrf2 Pathway: Enhancing antioxidant defenses.

• Inhibition of COX-2 and LOX: Anti-inflammatory actions.

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

  • [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

3) Impact on Klotho

A direct association between upregulating Nrf2 and its resulting increase of its anti-inflammatory and antioxidant properties, has been shown to correlated with increasing systemic levels of Klotho.

4) Safety Profile

RA is generally considered safe in typical dietary amounts. There may be some concern at higher doses, though the evidence is limited.

5) Oral Bioavailability

Oral bioavailability is considered low due to its metabolism in the gut and liver, leading to the rapid formation of metabolites.

6) Plasma Half-Life

The exact half-life of RA in human plasma is not well-documented. Further studies would be required to ascertain this information.

7) Additive, Complementary, or Synergistic

RA may act synergistically with other antioxidants and polyphenolic compounds, including:

• EGCG

• Curcumin

• Resveratrol

8) Antagonistic

There are no widely recognized antagonistic effects of RA with other active agents.

9) Diseases Impacted by Active Agent

RA has been studied for its potential benefits in:

• Cancer

• Inflammatory Conditions

• Neurodegenerative Disorders (e.g., Alzheimer's)

• Liver Disorders

10) Human Clinical Trials of Active Agent

Few human clinical trials have been conducted specifically on RA, with most research focused on preclinical studies and in vitro models. Some clinical trials have evaluated herbal preparations containing RA.

11) Known Anti-Aging Effects Attributable to Active Agent

RA's anti-aging effects may be attributed to:

• Reduction in Oxidative Stress: Through its potent antioxidant properties.

• Modulation of Inflammatory Responses: Potential in managing chronic inflammation, a critical factor in aging.

• Neuroprotective Actions: Potential to mitigate age-related cognitive decline.

12) References

Antioxidant and Anti-inflammatory Effects

Peake, P. W., Pussell, B. A., Martyn, P., Timmermans, V., & Charlesworth, J. A. (1991). The inhibitory effect of rosmarinic acid on complement involves the C5 convertase. International journal of immunopharmacology, 13(7), 853-857.

Neuroprotective Effect

Al-Sereiti, M. R., Abu-Amer, K. M., & Sen, P. (1999). Pharmacology of rosemary (Rosmarinus officinalis Linn.) and its therapeutic potentials. Indian journal of experimental biology, 37(2), 124-130.

Pharmacokinetics and Bioavailability

Khojah, H. M. et al. (2018). Pharmacokinetics of Rosmarinic Acid in Rats Is Altered by Herbal Teas Rich in Polyphenols. Planta medica, 84(06), 379-385.

Inhibition of NF-κB Pathway and Activation of Nrf2 Pathway

Osakabe, N. et al. (2004). Rosmarinic acid inhibits epidermal inflammatory responses: anticarcinogenic effect of Perilla frutescens extract in the murine two-stage skin model. Carcinogenesis, 25(4), 549-557.

Synergistic Effects with Other Antioxidants

Yoon, J. H., Baek, S. J. (2005). Molecular targets of dietary polyphenols with anti-inflammatory properties. Yonsei Med J, 46(5), 585-96.

Effects on Liver Disorders

El-Tantawy, W. H. (2016). Antioxidant effects of Spirulina supplement against lead acetate-induced hepatic injury in rats. Journal of Traditional and Complementary Medicine, 6(4), 327-331.

Anti-Aging Effects

Rašković, A., Milanović, I., Pavlović, N., Ćebović, T., Vukmirović, S., & Mikov, M. (2014). Antioxidant activity of rosemary (Rosmarinus officinalis L.) essential oil and its hepatoprotective potential. BMC complementary and alternative medicine, 14, 225.

Salvia miltiorrhiza

Scutellarein

SelInum

Senolytics

Shan Yao (Chinease Yam)

Shenkang Sinensetin

Sodium Bicarbonate

[2019] Bicarbonate Supplement Restores Urinary Klotho Excretion in Chronic Kidney Disease: A Pilot Study

[2023] The Effect of Sodium Bicarbonate Supplementation on Serum Alpha Klotho in Chronic Kidney Disease Patients Stage 3b to 4

Sodium butyrate

Spermidine

Sulforaphane (broccoli, broccoli sprouts)

Tangeritin

Taurine

Troglitazone

Ursolic Acid (Rosemary Acid (GABA agnost)

Valsartan

Valsartan (Angiotensin II Receptor Blocker (ARB)

VIT B (Complex)

VIT B12

Vit C

VIT D / (VDRAs)

6) [₪]  Vitamin D [14, 21] : is known to directly up-regulate the Klotho gene and increase systemic levels of soluble or α-Klotho.  The active form of Vitamin D (calcitriol) has been shown to upregulate Klotho expression. Vitamin D forms a complex with Klotho and FGF23 to regulate phosphate metabolism. Vitamin D binds to the vitamin D receptor complex (VDR), and this complex interacts with specific DNA sequences known as vitamin D response elements (VDREs) present in the promoter region of the Klotho gene, stimulating its transcription and increasing Klotho production. Vitamin D enhances the expression of FGF23, which in turn forms a complex with membrane Klotho in the kidneys. In our study, vitamin D supplementation caused higher levels of klotho compared to control group which possibly meant that vitamin D increased mRNA levels due to transcriptional activation of klotho. The FGF23/Klotho complex activates downstream signaling pathways that also enhance the expression of Klotho.

[2020] Effect of vitamin D supplementation on klotho protein, antioxidant status and nitric oxide in the elderly- A randomized, double-blinded, placebocontrolled clinical trial

Vitamin D (10-7) addition to the incubation medium of cardiomyocytes and neurocytes resulted in the increase of Klotho protein content by 56% on average, with 36% and 42% reduction of Ntz concentration, respectively. The registered effects of vitamin D are explained with its direct stimulating of the expression and synthesis of Klotho protein and limiting FGF23 hyperproduction.

1) Biological Profile

Vitamin D is a fat-soluble vitamin that exists in two main forms: Vitamin D2 (ergocalciferol) and Vitamin D3 (cholecalciferol). It's primarily involved in calcium homeostasis and bone metabolism but has diverse effects on immune modulation, cell growth, inflammation, and neuromuscular function.

2) Molecular Pathways and Mechanism of Action

• Vitamin D Receptor (VDR): Vitamin D acts by binding to the VDR, a nuclear receptor that regulates gene expression. VDR interacts with retinoid X receptors (RXRs) and forms a complex that binds to Vitamin D response elements in DNA.

• Calcium Homeostasis: Vitamin D promotes intestinal absorption of calcium and phosphate, acting with parathyroid hormone (PTH) to maintain serum calcium levels.

3) Human Clinical Trials of Active Agent

Various clinical trials have examined the effects of Vitamin D supplementation on bone health, immunity, cancer prevention, and cardiovascular diseases. Some studies indicate a positive effect on immune function and a potential reduction in the risk of chronic diseases, but results have been mixed.

4) Known Anti-Aging Effects Attributable to Active-Agent

Vitamin D's anti-aging effects might stem from its role in:

• Inflammation Reduction: Vitamin D may modulate cytokine production and reduce inflammation, a key factor in aging.

• Cellular Senescence: Some evidence suggests that Vitamin D might slow cellular aging through telomere length preservation.

• Metabolic Regulation: Potential regulation of insulin sensitivity and metabolic syndrome, linked to aging.

• Neuroprotection: Possible protective effects against neurodegenerative diseases.

5) Safety Profile

Vitamin D is generally safe when taken within recommended limits, but excessive intake can lead to toxicity, with symptoms like hypercalcemia, kidney stones, nausea, and weakness.

6) Bioavailability

Vitamin D3 has a higher bioavailability compared to D2. It can be synthesized in the skin from UVB radiation or obtained through diet and supplements.

7) Plasma Half-Life

The half-life of Vitamin D is relatively long, ranging from 15 to 50 days, depending on factors like binding to serum proteins and individual metabolism.

8) Impact on Klotho and Other Aging-Related Proteins

Vitamin D's role in regulating the expression of the Klotho gene is an area of interest in aging research. Some studies indicate that Vitamin D might enhance Klotho expression, potentially influencing aging through effects on mineral metabolism, cardiovascular health, and other pathways.

9) Diseases Impacted by Active Agent

Vitamin D is vital for:

• Bone health (osteoporosis, rickets)

• Immune function

• Potential reduction in risk for certain cancers, cardiovascular diseases, and autoimmune disorders

10) Additive, Complementary, or Synergistic

Vitamin D may have synergistic effects with calcium supplementation in bone health. Its deficiency might exacerbate chronic conditions related to aging.

VIT E {39}

VIT K

Wogonin

Zinc