Klotho: Become Smarter And Live Longer With 50+ Ways To Increase Klotho

Alpha-, Beta-, And Gamma-Klotho's Role In Longevity, Intelligence, Muscle Strength, And Cancer

Klotho may be one of our humans' natural adaptogens by its ability to help regulate cellular stress. R R

In this post, we will discuss its role in longevity, muscle strength, cancer, cognition, and neurotransmitter balance.

 
 http://www.sciencedirect.com/science/article/pii/S0303720716301575

http://www.sciencedirect.com/science/article/pii/S0303720716301575

 

Basics

Klotho is an anti-aging protein that is mostly secrete by the kidneys, the brain, and the thyroid. R

It plays a major role in regulating kidney function and vascular health. R

The name for the klotho gene was named after "the Spinner" (Clotho from Greek mythology), the goddess who spins the thread of life. R

Conditions Associated With Klotho Activity

Low Activity Of Klotho:

  • Acetylcholine and Nitric Oxide Dysregulation R
  • Aging (highly accelerated) R
  • All-Cause Mortality R
  • Anemia R
  • Anorexia R
  • Atherosclerosis (as well as calcification of the arteries) R R
  • Bone Loss (such as osteoporosis and low bone mass) R R
  • Cancer R
  • Cataracts R
  • Chronic Stress R
  • Depression R
  • Diabetes R
  • Glaucoma R
  • Growth Hormone Deficiency R
  • Kidney Disease (such as CKD and electrolyte imbalances) R R R
  • Kidney Transplant R
  • Hyperphosphatemia R
  • Hyperparathyroidism R
  • Hypertension R
  • Impaired Cognition (such as Alzheimer's Disease) R
  • Inflammatory Bowel Disease R
  • Lung Damage R
  • Multiple System Atrophy R
  • Pseudoexfoliation Syndrome R
  • Rheumatoid Arthritis R
  • Sarcopenia R
  • Skin Atrophy (such as scleroderma) R
  • Stroke R
  • Vascular Disease (such as coronary artery disease) R R

High Activity Of Klotho:

  • Acromegaly R
  • Alcoholism R
  • Bipolar Disorder (can be low as well, as it seems to be dysregulated) R R
  • Multiple Sclerosis R
  • Polycystic Ovarian Syndrome R

Benefits Of Increased Klotho

1. Improves Cognition

 
brain-2062048_1280.jpg
 

Klotho levels have been shown to be lower in patients with Alzheimer's Disease (AD). R

In studies where mice were unable to produce klotho, they displayed impaired abilities to form new memories and associations. R R

Even in healthy mice, young mice, klotho enhances brain function and Long Term Potentiation (LTP). R

In studies where mice had high levels of alpha-synuclein (protein in their brain found of AD and Parkinson's Disease (PD) patients), klotho was able to improve their memory and synaptic plasticityR

Also in models of PD, klotho can protect dopamine in the brain. R

In humans, higher levels of klotho has been associated with enhanced cognition, better learning, and memory skills. R

Having a genetic predisposition to produce more klotho (discussed below) is also associated with a having a higher intelligence quotient (IQ). R

Klotho also increases myelination in the brain and may be beneficial for patients with Multiple Sclerosis (MS). R

2. May Increase Longevity

Klotho declines with age. R

In humans, low circulating klotho has been shown to be correlated with a significantly higher risk of death. R

In studies of mice that were genetically modified to overexpress klotho, they had significantly extended life-spans (by 20-30%). R

One way it is able to do this is by decreasing levels of Insulin-Like Growth Factor-1 (IGF-1) signaling. R

Another way it may do this is by klotho's ability to reduce inflammation and oxidative stress. R R

3. May Prevent Cancer

Klotho can surpress tumor formation. R R

Increasing expression of klotho may help with:

  • Bone Cancer R
  • Brain Cancer R
  • Breast Cancer R
  • Colon Cancer R
  • Gastric Cancer R
  • Kidney Cancer R
  • Liver Cancer (controversial, see belowR
  • Lymphatic Cancer R
  • Skin Cancer R

4. May Improve Exercise Performance

 
 

Regular aerobic exercise could increase plasma Klotho levels. R

We lose around 20-40% of both skeletal muscle mass and strength from 20 to 80 years old. R R

Klotho may improve strength as high levels of klotho is correlated with total body muscle strength. R

Thus, Klotho may help with sarcopenia (muscle loss). R

One way it helps with preventing muscle loss is by decreasing the expression of Transforming Growth Factor-1 (TGF-b1) and increasing the expression of Growth Hormone (GH). R R

Another way is possibly by it's ability to modulate stem cells and improve tissue regeneration. R R R

Klotho may also improve gait. R

5. May Improve Vision

Klotho helps the retina keep homeostasis by improving melanin production in the eye. R

Klotho may prevent age-related retinal degeneration and lens associated conditions such as cataractsR R

By increasing levels of klotho, latanoprost may be able to improve symptoms of glaucoma. R 

6. Protects Against Kidney Diseases

Klotho regulates calcium homeostasis in the blood and mainly the kidneys. R R

Upregulation of klotho may prevent fibrosis in the kidneys. R

Klotho may also improve electrolyte imbalances and abnormal amounts of proteins in the blood. R R

7. Protects The Vascular System

Klotho may prevent vascular disease by its ability to regulate antioxidants. R R R

For example, klotho is able to reduce the oxidative stress from oxidized LDL (ox-LDL). R

In humans, higher klotho levels were associated with lower likelihood of Cardiovascular Disease (CVD). R

Klotho may be able to protect the vascular system from a diet high in fat. R

Low levels of klotho may increase the chances of developing high blood pressure and salt sensitivity. R

Klotho may also protect against calcification of the arteries by reducing phosphorus. R

It can also improve the production of new blood cellsblood flow and may be able to replace statin therapies. R R

8. Protects The Bones

Decreased Klotho levels are associated with a decrease in Bone Mineral Density (BMD). R

9. May Help With Lung Disease

Klotho may help mitigate age-related lung disease. R

It may also help with fibrosis in the lungs. R

Downsides Of Klotho

Bile Acids, Gut Microbiome, And Brown Fat

 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396514/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396514/

 

Decreased klotho may not be all bad. 

For example, mice that are unable to produce normal amounts of klotho have better abilities at regulating body temperature, better bile acid synthesis, smaller gallbladders, and more brown fat (BAT). R

They are also protected against non-alcoholic fatty liver diseases and have better insulin sensitivity. R

Weight

Klotho upregulates Peroxisome Proliferator-Activated Receptor-Gamma (PPAR-gamma), which may stimulate weight gain. R

For example, genetically abolishing Klotho function in mice results in leaner mice. R

Although, when beta-klotho binds to fibroblast growth factor (FGF-23), it helps  stimulates insulin sensitivity and glucose metabolism, causing weight loss. R

Insulin Resistance

Klotho is usually low in models of insulin resistance, but paradoxically klotho can reduce insulin and glucose in the blood thus increasing the chances of developing insulin resistance (as well as IGF-1 resistance) and possibly hypoglycemia. R

This may mean inhibiting klotho may be good for high glucose levels in those unable to produce insulin. R

Although, some studies have shown Klotho may enhance glucose-induced insulin secretion by up-regulating plasma membrane levels of TRPV2 and thus glucose-induced calcium responses. R

(speculation) The insulin resistance that klotho may induce may actually help cells age slower by inhibiting apoptosis from oxidative stress. 

For example, in models of type 1 diabetes, klotho can protect pancreatic beta-cells from death. R

Also, in models of type 2 diabetes, klotho can decrease hyperglycemia, enhance glucose tolerance, and increase pancreatic beta-cell numbers. R

Cancer

In the benefits above we discussed Klotho and beta-klotho (βKlotho), but gamma-klotho (γKlotho) may be associated with breast cancer. R

Klotho may increase the progression of liver cancer. R

Vitamin D

If you are genetically predisposed to produce low klotho, then supplementing Vitamin D may reduce dopamine in the brain. R

This is because klotho inhibits 1-α hydroxylase, the enzyme responsible for the production of active vitamin D (1,25 dihydroxy vitamin D3). R

Ways To Increase Klotho

It's better to have this protein increased.

 
 

Diet:

Lifestyle:

  • Caloric Restriction R
  • Exercise - medium amounts of aerobic exercise can do it significantly (compared to large amounts) and so can single bouts of exercise, but it is not as significant. It should be noted that having a low BMI helps raise klotho more in single bouts of exercise, whereas having a high BMI may have no effect with single bouts of exercise. R R R R R
  • Smoking (ironic correlation) R
  • Sun Exposure (without sunscreen) R

Supplements: 

Probiotics:

Hormones:

  • Growth Hormone R
  • Insulin R
  • Melatonin R
  • Testosterone R
  • Triiodothyronine (T3) R R

Drugs/Chemicals:

  • AST-120 R
  • Atrasentan R
  • Avandia R
  • Azacytidine R
  • Compound H R
  • Fluoride R
  • Klotho (inject it, but it cannot pass the blood-brain barrier) R
  • Lipitor R R
  • Troglitazone R
  • Tubastatin A R
  • Xalatan (Latanoprost) R

Pathways:

Having low klotho downregulates SIRT1, but increasing SIRT1 seems to make up for some of the vascular benefits of klotho, so it's probably a good idea to increase SIRT1 as well. R

  • Increasing IGF-1 R R
  • Increasing Intermedin1-53 R
  • Increasing PPAR-gamma R R R
  • Inhibiting AT1R R
  • Inhibiting FGF23
  • Inhibiting HDAC (3, 6) R R R
  • Inhibiting HMG-CoA reductase R

What Reduces Klotho?

  • Adiponectin R
  • Angiotensin II activation R
  • Asbestos R
  • Doxorubicin R
  • Estrogen R
  • Hmgb1 activation R
  • Hypervitaminosis R
  • Ketogenic Diet R
  • Nephrectomy R
  • NMDA Inhibition R
  • Stress and Depression R
  • Timp-3 Inhibition R
  • TGFβ R

Klotho Levels

Since klotho declines with age, it's probably a good idea to keep it elevated. R

A healthy range will be above 700 pg/mL. R R

For example, in humans having a greater grip strength was positively correlated with plasma klotho at a threshold of <681 pg/mL. R

You can can test your levels here (soon).

Mechanism Of Action

Simple:

  • Increases cAMP R
  • Increases C/EBPalpha R
  • Increases C/EBPdelta R
  • Increases FGF-23 R
  • Increases FoxO R
  • Increases GH R
  • Increases GluN2B R
  • Increases HO-1 R
  • Increases HSP70 R R
  • Increases IL-10 R R
  • Increases LC3 R
  • Increases MITF R
  • Increases MBP R
  • Increases Mn-SOD R
  • Increases NMDA R
  • Increases NO R
  • Increases NRF2 R R
  • Increases PCNA R
  • Increases Pdx-1 R
  • Increases Prx-1 R
  • Increases PPAR-gamma R
  • Increases ROMK R
  • Increases TYR R
  • Reduces α-SMA R
  • Reduces Aldosterone R
  • Reduces Ang II R
  • Reduces β-catenin R
  • Reduces IGF-1 R
  • Reduces IL-6 R
  • Reduces IL-12 R
  • Reduces Insulin R
  • Reduces JAK2 R
  • Reduces LOX-1 R
  • Reduces M1 mAChR R
  • Reduces Nox2 R
  • Reduces STAT3 R
  • Reduces TGF-B1 (signaling, not expression) R
  • Reduces TNF-alpha R
  • Reduces VEGF R R
  • Reduces Wnt R

Advanced:

  • Klotho is expressed mainly in the kidneys (strongest expression), parathyroid glands (strong), brain (strong), choroid plexus, aorta, colon, thyroid gland (strong), pancreas, liver, cerebrospinal fluid, blood, bones (low), skin (low) and testes. R R R R R R R
  • 3 homologs of Klotho, α, β, γ and have been identified, with β-Klotho sharing 41% amino acid identity with α-Klotho. R
  • γKlotho may enable cancer cells to cope with an oxidative environment. R
  • There are two types of klotho - Membrane Bound and Circulating
    • Membrane Bound - αKlotho can bind to multiple FGF receptors, and that the Klotho-FGF receptor complex binds as a co-receptor for to fibroblast growth factor (FGF-23, a hormone produced by osteocytes and is a critical circulating hormone involved in phosphate metabolism) with much higher affinity than either the FGF receptor or Klotho alone. R R
    • Klotho functions as a coreceptor for FGF23, which downregulates the expression of 1,25-dihydroxyvitamin D3 and phosphate reabsorption. R
    • Serum soluble α-Klotho concentrations are inversely correlated with serum FGF23. R
    • FGF23 suppresses PTH secretion by a Klotho independent pathway involving calcineurin. R
    • In the heart, the Klotho independent FGF23 signaling is mediated through FGFR4. R
    • Circulating - After binding, it loses it's membrane domain and enters circulation as soluble Klotho (sKl), acting as a hormone with anti-aging and anti-oxidative stress properties. R R
  • Klotho upregulates nitrous oxide (NO) production and inhibits angiotensin II (Ang II)-induced Reactive Oxygen Species (ROS) production within endothelial cells. R
  • It treatment significantly downregulates protein expression of Ang II receptor type I (AT1R) but not type II (AT2R). R
  • It also decreases stress in the endoplasmic reticulum (ER). R R
  • Klotho enhances Mn-SOD expression (~2x), via activation of the cAMP signaling pathway and activation of the FoxO forkhead transcription factors that are negatively regulated by insulin/IGF-1 signaling. R R
  • In the heart, soluble klotho significantly induces expression of NRF2, heat shock protein 70 (HSP70) and the antioxidant enzymes heme oxygenase (HO-1) and peroxiredoxin-1 (Prx-1) and enhances glutathione levels. R R
  • Klotho inhibits angiotensin II-induced reactive oxygen species production. R
  • Klotho also activates the Transient Receptor Potential ion channel TRPV5 and TRPV6, and helps with calcium reabsorption. R R R
  • Within the brain, Klt is particularly expressed to a greater extent in the choroid plexus (CP). R
  • Also in the brain, low klotho levels may increase lipid and DNA oxidization. R
  • It also regulates hippocampal CA1 synaptic plasticity. R
  • In multiple sclerosis, klotho and FGF-23 seem to act in positive feedback loop to protect against demylenation and BBB permeability by mediators secreted by the CP. R
  • Klotho works party by enhancing N-Methyl-D-Apartate (NMDA) receptor's actions, especially in mice with amyloid-beta plaques. R R
  • In fat cells, Peroxisome Proliferator-Activated Receptor-Gamma (PPAR-gamma) induces expression of the β-Klotho homolog, and conversely, β-Klotho upregulates PPAR-ϒ synthesis. R R
  • The mRNA expression of adipocyte differentiation markers, such as CCAAT/enhancer-binding protein (C/EBP)alpha, C/EBPbeta, C/EBPdelta, PPAR-gamma, and fatty acid binding protein 4, was decreased by klotho suppression, and increased 1.9- to 3.8-fold by klotho overexpression. R
  • Klotho may prevent kidney fibrosis by its ability to decrease (inhibit) the signaling (not expression) of TGF-beta 1. R
  • In mice, klotho treatment at relatively low concentrations (0.1 ng/mL) can increase growth hormone secretion by 2 fold . R
  • In b cell lypmohmas, upregulation of Klotho resulted in declined activation of IGF-1R signaling, accompanied with decreased phosphorylation of its downstream targets, including AKT and ERK1/2. R
  • In the eye, klotho regulates mealnogenesis in the retinal pigment epithelium's (RPE) by expression of microphthalmia transcription factor (MITF) and tyrosinase (TYR). R

Genetics

KLOTHO

  • rs9536314 (I'm TT)
    • TT is most common 
    • GG associated with lower cognitive function with age R R
    • GG associated with higher risk of dementia in men followed by GT then TT R
    • GT associated with increased longevity, improved executive function/cognition, improved cardiovascular health, improved kidney health, and having a bigger brain R R
    • GT is associated with higher klotho levels, whereas GT and TT are associated with less klotho R
    • Unknown allele associated with healthy aging and longevity by inhibiting the insulin/ IGF-1 signaling pathway R
  • rs1207568 (I'm CC)
    • AA and GA polymorphisms were related with colorectal cancer risk, AA had higher risk R
    • AA and GA genotype subjects had a significantly lower risk of cognitive impairment than GG in Chinese nonagenarians and centenarians R
  • rs211239 (I'm GA)
    • G (major) is associated with sickle cell disease R
    • A (minor) associated with osteoporosis R
    • Unknown allele associated with sickle cell disease R
  • rs2249358 (I'm GA)
    • G associated with odds ratio is 2.6 (CI: 1.4-5.5) of sickle cell anemia R R
  • rs577912 (I'm TG)
    • G (major) is associated with a higher risk of death in the 1st year of end-stage renal disease R
    • Unknown allele associated with sickle cell anemia R
  • rs648202 (I'm CC)
    • Unknown allele associated with sickle cell anemia R
    • Unknown allele associated with abnormal vitamin D metabolism R
  • rs650439 (I'm TA)
    • T (minor) is associated with artery thickening R
    • Unknown allele associated with non-diabetic end-stage renal disease in African Americans R
  • rs9527025
    • Unknown allele associated with Sickle Cell Disease R
    • Unknown allele associated with Spontaneous preterm birth R

More Research

  • Klotho can protect against the cell toxic effects of paraquat, a toxic herbicide. R