Klotho

What is it?

Klotho is an enzyme that in humans is encoded by the KL gene.^[5] and it has many health benefits, including vascular health, inflammation, and aging. Unfortunately the levels of Klotho fall as you grow older.

“Klotho” is actually several molecules including α-klotho, β-klotho, and γ-klotho.^[6] α-klotho activates FGF23, and β-klotho activates FGF19 and FGF21.^[7] When the subfamily is not specified in a research paper, they likely mean α-klotho because this was discovered first.

You can view Klotho as existing in 2 forms:

• Membrane-bound Klotho: Found on the cell surface, it acts as a co-receptor for certain fibroblast growth factors (FGFs), influencing cellular processes.

• Soluble Klotho: Released from the membrane-bound form, it circulates in the blood and has broader systemic effects.

Why do I care?

α-klotho is highly expressed in the brain, liver and kidney^[9] β-klotho in the liver^[10][9] γ-klotho in the skin.^[9]

Klotho has several functions, including:

• Regulation of mineral metabolism: Particularly phosphate and calcium.

• Antioxidant activity: Protecting cells from oxidative damage.

• Anti-inflammatory effects: Reducing inflammation.

• Insulin sensitivity: Helping cells respond properly to insulin.

• Neuroprotective effects: Supporting brain health.

Your body makes Klotho, but levels fall as you age. Also AGE that builds up may decrease klotho production as well. [4] So the decline of Klotho when aging is a concern and this decline has been linked to many age-related diseases and the overall aging process itself.

There is interest among researchers about whether restoring these levels, will restore youthful function, and experiments have been done on cells, animal models, and humans. [12] Here's a breakdown of the current evidence:

1. Human Cells (in vitro studies):

• Positive effects: Many studies using cell cultures have demonstrated that adding soluble Klotho can have positive impacts on various cellular processes. This includes:

  • Increased cell survival and proliferation.

  • Reduced oxidative stress and inflammation.

  • Improved cellular function in aged cells.

  • Enhanced insulin sensitivity in cells.

• Limitations: Cell studies are useful for understanding basic mechanisms, but they don't necessarily translate directly to whole organisms. They can show what might happen, but aren't proof of effects in vivo.

2. Animal Models (in vivo studies):

• Promising results: Animal studies, particularly in mice, have shown some impressive effects of increasing Klotho levels:

  • Extended lifespan: In some studies, mice with genetically increased Klotho levels or treated with soluble Klotho showed an extended lifespan. [11]

  • Improved cognitive function: Some studies have seen better cognitive performance, including improved learning and memory, in animals with higher Klotho levels.

  • Improved physical health: They may also have improved markers of health, such as better cardiovascular function, increased muscle strength, and reduced age-related frailty.

  • Disease prevention: In some studies, higher Klotho has reduced the severity or incidence of age-related diseases like kidney disease, osteoporosis, and cardiovascular problems.

• Important Considerations:

  • Delivery methods: Research uses various methods of Klotho supplementation including genetic manipulation, injection of soluble Klotho, or gene therapy. The effectiveness might vary depending on the delivery method and dosage.

  • Mouse models may not fully translate: Results seen in mice may not always apply to humans.

  • Complex interactions: Aging is complex and likely involves multiple factors beyond Klotho. Therefore, Klotho is probably not a single 'cure' for aging.

3. Humans:

• Early Stages: Research in humans is much less advanced compared to cellular and animal studies, and we're just beginning to understand the potential benefits of Klotho supplementation.

• Observational Studies: Studies have found associations between higher circulating Klotho levels and better cognitive function, lower risk of cardiovascular disease, and improved overall health in humans. However, association does not prove causation - higher klotho levels could be a result of health, not the cause of it.

• Intervention Studies: There is limited research on the safety and efficacy of directly supplementing Klotho in humans. Some very small, early clinical trials are underway and are investigating the feasibility and effects of administering Klotho, but results are very preliminary.

• Challenges: There are major hurdles:

  • Delivery: Klotho is a large protein and does not easily cross cell membranes and the blood-brain barrier. Oral delivery is likely not effective, and injection is cumbersome.

  • Dosage and Safety: Optimal dosages and long-term safety in humans are unknown.

  • Interactions: We need to understand how Klotho interacts with other bodily systems.

  • Individual Differences: People may respond differently to Klotho based on genetics, age, or health status.

• We do not currently have good evidence that supplementing Klotho has a beneficial effect on aging in humans.

• Important Note: Currently, there is no FDA-approved Klotho supplement available, and you should be very cautious of products claiming to be Klotho supplements. More research is necessary before any recommendations for Klotho supplementation for anti-aging purposes can be made. Consult with a healthcare professional before considering any experimental treatments.

Where could I find it? Sources of Klotho.

Since more than half of FDA-approved drugs are natural products and their derivatives [8] so it should not be surprising that you can find a chemical in a plant that activates Klotho. In fact, there are several:

1.PPAR-γ agonists like thiazolidinediones increased klotho in HEK292 mammal cells in culture ( troglitazone and ciglitazone ) [1] [3] These are prescription drugs.

2.Berberine upregulated Klotho expression and protected against cardiac senescence. [5] Berberine is a chemical found in many plants like European barberry, goldenseal, goldthread, Oregon grape, phellodendron, and tree turmeric. Historically it has been used to treat diabetes. WebMD generally says that it is safe but with caveats. For example it is known to react poorly with many drugs. [10]

credit https://doi.org/10.1016/j.biopha.2022.113097.

3.Cycloastrogenol.

Cycloastragenol activation of telomerase improves β-Klotho protein level and attenuates age-related malfunctioning in ovarian tissues [6]

A comprehensive review of cycloastragenol: Biological activity, mechanism of action and structural modifications [7]

credit https://www.sciencedirect.com/science/article/pii/S2772417422000322

Cycloastragenol (CAG) is a sapogenin of Astragaloside IV (AG-IV), isolated from the dried roots of legumes Astragalus mongolica or Astragalus membranaceus. Cycloastragenol has a steroidal skeleton of tetracyclic triterpene and possess diverse pharmacological activities such as anti-aging, anti-inflammatory, anti-fibrosis, pro-wound healing, liver protection and endothelial protection.

cycloastragenol

In addition, cycloastragenol is the only telomerase activator reported in natural products, which is closely related to MAPK and PI3K/Akt signaling pathways.[7]

Astragalus mongholicus credit www.plantarium.ru

So one of the last questions in my mind are these. Does the “Astragalus Root Herbal Tea” for sale on the Internet, actually contain cycloastrogenol, and how much would be required to have any real biological effect? One cup? Gallons?

4. Spirolactone.

Spirolactone is a prescription drug, commonly used for a diuretic (water pill) that prevents your body from absorbing too much salt and keeps your potassium levels from getting too low. Spironolactone is used to treat heart failure, high blood pressure (hypertension), or hypokalemia (low potassium levels in the blood). It can be unsafe for many people, like if you have kidney or liver issues. It is also been shown to raise Klotho levels. [9]

Summary

To recap, Klotho is an important molecule for health, but its levels drop as you age, and there is some evidence that restoring levels is helpful. So although you can get it in gene therapies or herbs, there is no conclusive evidence yet that you should.

References.

[1] Hong Zhang, Yuanyuan Li, Yanbo Fan, Jing Wu, Beilei Zhao, Youfei Guan, Shu Chien, Nanping Wang,
Klotho is a target gene of PPAR-γ, Kidney International,Volume 74, Issue 6,2008,Pages 732-739,ISSN 0085-2538,
https://doi.org/10.1038/ki.2008.244.

[2] Troglitazone Improves Endothelial Function and Augments Renal klotho mRNA Expression in Otsuka Long-Evans Tokushima Fatty (OLETF) Rats with Multiple Atherogenic Risk Factors

Takahiro YAMAGISHI, Yuichiro SAITO, Tetsuya NAKAMURA, Shin-ichi TAKEDA, Hiroyoshi KANAI, Hiroyuki SUMINO, Makoto KURO-O, Yo-ichi NABESHIMA, Masahiko KURABAYASHI, Ryozo NAGAI

https://www.jstage.jst.go.jp/article/hypres/24/6/24_6_705/_article/-char/ja/

https://www.jstage.jst.go.jp/article/hypres/24/6/24_6_705/_pdf

[3] https://en.wikipedia.org/wiki/Ciglitazone

[4] https://www.sciencedirect.com/science/article/pii/S0944711318303118

Wei-Chih Kan, Jean-Yu Hwang, Lea-Yea Chuang, Jinn-Yuh Guh, Yi-Ling Ye, Yu-Lin Yang, Jau-Shyang Huang,

Effect of osthole on advanced glycation end products-induced renal tubular hypertrophy and role of klotho in its mechanism of action,

Phytomedicine, Volume 53,2019,Pages 205-212,ISSN 0944-7113,

https://doi.org/10.1016/j.phymed.2018.09.030.

(https://www.sciencedirect.com/science/article/pii/S0944711318303118)

[5] Cong Li, Shuang Jiang, Hengfei Wang, Yuhong Wang, Yanxing Han, Jiandong Jiang,

Berberine exerts protective effects on cardiac senescence by regulating the Klotho/SIRT1 signaling pathway,

Biomedicine & Pharmacotherapy,Volume 151,2022,113097,ISSN 0753-3322,

https://doi.org/10.1016/j.biopha.2022.113097.

(https://www.sciencedirect.com/science/article/pii/S0753332222004863)

[6] https://www.sciencedirect.com/science/article/pii/S0047637422001385

[7] https://www.sciencedirect.com/science/article/pii/S2772417422000322

[8] https://onlinelibrary.wiley.com/doi/10.1111/cpr.12190

[9] https://www.drugs.com/spironolactone.html

[10] https://www.webmd.com/vitamins/ai/ingredientmono-1126/berberine

[11] https://pmc.ncbi.nlm.nih.gov/articles/PMC6962016/

[12] https://www.sciencedirect.com/science/article/pii/S1568163722002082

Disclaimer. Last updated November 17, 2024

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Abbreviations

AMPK   5′AMP-activated Protein Kinase
CAG Cycloastragenol
EGF Epidermal Growth Factor
EpSCs Epidermal stem cells
ERK Extracellular Regulated Protein Kinases
FGF Fibroblast Growth Factor
FGFR Fibroblast Growth Factor Receptor
IL-1β Interleukin-1β
IGF Insulin-like Growth Factor
KLB β-Klotho
MAPK Mitogen-activated Protein Kinase
MEK ERK kinase
NAFLD Non-alcoholic fatty liver disease
NASH/MASH Non-alcoholic steatohepatitis
NF-κB Nuclear factor kappa B
PARP Poly ADP-ribose polymerase
PDK 3-Phosphoinositide-dependent protein kinase
PI3K Phosphatidylinositol 3-kinase
RAGE/AGE Advanced Glycosylation End-product Specific Receptor
ROS Reactive Oxygen Species
SIRT1 Sirtuin 1
TERT Telomerase reverse transcriptase
TNF-α Tumor necrosis factor-α
TXNIP Thioredoxin interacting protein
VEGF Vascular Endothelial Growth Factor