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Klotho is a protein that can make you more intelligent and live longer.  Read on about how to increase it.

If you want to interpret your genes, you can use SelfDecode.



Klotho is a protein that circulates in the blood and brain/spine throughout life (R).  It declines with aging in conjunction with cognitive deficits (RR2R3).

Klotho increased intelligence by as much as 3% or 6 point IQ boost (R).

Klotho also helps you regenerate muscle (by inhibiting TGF) (R).

Klotho is an anti-aging and health-promoting protein.   When increased, it extends lifespan (R) and when it’s decreased, it decreases lifespan (R).

Klotho diminishes age-related heart disease (R).

Klotho suppresses insulin pathways (R).

Klotho suppresses the production of Calcitriol/Active vitamin D (decreases 1alpha-hydroxylase gene expression) (R).

Klotho significantly enhances our antioxidant balance (specifically the thioredoxin/peroxiredoxin (Trx/Prx) system with the greatest effect on the induction of Prx-2) (R).

Mouse Studies on Klotho

UPDATED 032414 Klotho Graphical Abstract

Mice bred for higher levels of Kloth0:

  • Had increased lifespan (between 19% and 31%) (R)
  • Were more resistant to oxidative stress (R)
  • Performed better in multiple tests of learning and memory (R)
  • Better memory, indicated by more long-term potentiation, a form of synaptic plasticity (R)
  • Had enhanced synapses and glutamate receptors (R)

Mice bred to have lower levels of Klotho experience:

  • Early postnatal death (R)
  • Less myelination (R)
  • Synapse shrinkage (R)
  • Cognitive impairment (R)
  • Infertility (R)
  • Osteoporosis (R)
  • Accelerated aging (R)
  • Heart disease (R)
  • Impaired vessel Nitric Oxide, less vasodilation and angiogenesis (R)
  • Increased production of Calcitriol/Active vitamin D and higher blood calcium and phosphorous, which might be the cause of premature aging in one study (R).
  • Increased ADH and Aldosterone (R). One study says that excessive formation of Calcitriol in Klotho-deficient mice results in volume depletion outside cells, which contributes significantly to the shortening of life span (R).

How to Increase Klotho

Screenshot 2015-01-06 22.59.14

  • Exercise – in both humans and mice (R)….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 cell secrete Klotho (R).
  • Calcitriol/Active vitamin D increases Klotho (R, R2). However, Vitamin D supplements apparently don’t work in humans to increase Klotho, even when calcitriol goes up (R). In dialysis patients, vitamin D supplements actually decrease Klotho (R).
  • Insulin increases klotho (R).  This is one downside to a really low carb diet.
  • PPARgamma activators (R, R2)
  • Statins/Red yeast rice (HMG -CoA reductase inhibitors) (R, R2) – might simply stabilize some part of the process after its production (R).
  • Activated charcoal by binding to a toxin that decreases klotho (Indoxyl sulfate) (R)
  • Gentian root extract– might simply stabilize some part of the process after its production (R),
  • Probiotics such as Acidophilus + L Lactis in aging mice (R).
  • Cordyceps reverses the Angiotensin II decrease klotho (R).
  • ACE inhibitors

What Decreases Klotho


The following decrease klotho:

  • Psychological stress and depression (R). Women under high chronic stress had low klotho compared with low-stress controls.  Depressed people had even lower klotho levels (R).
  • Inflammation (R)
  • Oxidative stress (such as H2O2) (R)
  • Angiotensin II (R)
  • Indoxyl sulfate (R), a product of protein degradation (R)
  • In dialysis patients, vitamin D supplements decrease Klotho (R)

Klotho SNPs

Get your 23andme to find out your Klotho Gene.  You must sign up for SelfDecode to see if you’re a high or low klotho producer.

The most significant Klotho SNP is:

  1. RS9536314

Other Klotho SNPs:

  1. RS211239
  2. RS2249358
  3. RS577912
  4. RS648202
  5. RS650439

Technical Aspects of Klotho


  • Increased total protein levels of the NMDAR subunit GluN2B (R). GluN2B enhances cognition (RR2R3) and dysfunction of this sub-unit contributes to Alzheimer’s (R,R2). Klotho elevation nearly doubled GluN2B levels in post-synaptic density (PSD) fractions in the mouse hippocampus (R)
  • Suppresses Wnt (R), Regulates ion channel clustering (R) and transport (R), Promotes FGF23 function (R)…

Health Tools I Wish I Had When I Was Sick

At SelfHacked, it’s our goal to offer our readers all the tools possible to get optimally healthy. When I was struggling with chronic health issues I felt stuck because I didn’t have any tools to help me get better. I had to spend literally thousands of hours trying to read through studies on pubmed to figure out how the body worked and how to fix it.

That’s why I decided to create tools that will help others cut down the guesswork:

  • Lab Test Analyzer – a software tool that will analyze your labs and tell you what the optimal values are for each marker — as well as provide you with actionable tips and personalized health and lifestyle recommendations to help you get there.
  • SelfDecode – a software tool that will help you analyze your genetic data from companies such as 23andme and ancestry. You will learn how your health is being impacted by your genes, and how to use this knowledge to your advantage.
  • SelfHacked Secrets – an ebook where we examine and explain the biggest overlooked environmental factors that cause disease. This ebook is a great place to start your journey if you want to learn the essential steps to optimizing your health.
  • SelfHacked Elimination Diet course – a video course that will help you figure out which diet works best for you
  • Selfhacked Inflammation course – a video course on inflammation and how to bring it down
  • Biohacking insomnia – an ebook on how to get great sleep
  • Lectin Avoidance Cookbook – an e-cookbook for people with food sensitivities
  • BrainGauge – a device that detects subtle brain changes and allows you to test what’s working for you
  • SelfHacked VIP – an area where you can ask me (Joe) questions about health topics

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  • Terrence Dowd

    GABA increases Klotho, human equivalent of the mouse dose is 30 – 50mg daily.
    Increasing levels of GABA in the brain can be done easily by adding Vitamin B6 to Glutamine preferably on empty stomach with water/juice. My dose has been 500mg – 1000mg Glutamine with 20 – 50mg B6, effect is very strong, not recommended if you have any public speak or socializing on the agenda 🙂

  • Nathan

    I was checking my friend’s raw data and he doesn’t have a RS9536314 in his file, wtf?

  • Judy Haise

    How do I find Plotho to ingest?

  • john reddick

    I find all that here very informative & would like to add that often overlooked is quality of sleep & functional breathing as well as eliminating/greatly diminishing daytime mouth-breathing as *fundamental* in maintaining adequate Klutho production & reductions of oxidative stresses.

  • carol close

    Mushrooms grown in sunlight increase Klotho by virtue of their vitamin D content. Cordyceps mushrooms increase and boost Klotho levels. (Journal of Central South University. Medical Sciences, April. 2009)


    Magnesium is indirectly involved in Klotho gene protein production. When blood serum calcium levels are somewhat below normal, magnesium reduces parathyroid secretion and increases parathyroid calcium cell receptor, the vitamin D receptor and Klotho gene protein. This suggests calcium intake should be limited and magnesium shortages should be avoided for healthy aging. (Nephrology Transplantation, February 2014).

  • carol close “Induction of Klotho Gene Expression by Natural Product Compounds and the Anti-aging Analysis”. Notopterygium incisum Ting., Semen Raphani and Epimdium biolba, EC50 of which is 128.90μg/ml, 3.57 mg/ml and 1.62 mg/ml respectively, were found to be able to activate the promoter of klotho gene. These results suggested that the extract of Notopterygium incisum Ting, could enhance the expression of klotho, protect cardio-vascular system, and increase the antioxidation and anti-aging activity. (So it is a combination of Notopterygium, radish seeds and horny goat weed together in these amounts to increase Klotho.)

    Delta sleep enhances growth hormone secretion which increases Klotho.. Rosemary, tryptophan, 5HTP plus GABA, ashwagandha, and gemnostemma enhance Delta sleep. Klotho: a novel biomarker for cancer Klotho has biological activity that includes regulatory effects on general metabolism and a more specific effect on mineral metabolism that correlates with its effect on aging. Klotho serves as a co-receptor for fibroblast growth factor (FGF), but it also functions as a humoral factor that regulates cell survival and proliferation, vitamin D metabolism, and calcium and phosphate homeostasis and may serve as a potential tumor suppressor. Moreover, Klotho protects against several pathogenic processes in a FGF23-independent manner. These processes include cancer metastasis, vascular calcification, and renal fibrosis. This review covers the recent advances in Klotho research and discusses novel Klotho-dependent mechanisms that are clinically relevant in aging and age-related diseases
    Klotho response to treatment with growth hormone and the role of IGF-I as a mediator.
    Klotho levels increased during GH treatment of pediatric GHD patients. This increase was associated with an increase in IGF-I levels. Furthermore, we showed, for the first time, a direct role of IGF-I in the regulation of klotho’s shedding which depends on activation of the AKT-mTOR pathway. Our findings add further support for the close association between klotho and the GH/IGF-I axis
    Rhein reverses Klotho repression via promoter demethylation and protects against kidney and bone injuries in mice with chronic kidney disease Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Klotho protein in kidney is implicated in calcium homeostasis which regulates localization of sodium phosphate cotransporters via parathyroid hormone. Klotho proteins not only function as a humoral factor, but also are implicated in hormonal regulation, which may explain why mutation of klotho gene results in a variety of phenotypes. Klotho expression in epithelial ovarian cancer and its association with insulin-like growth factors and disease progression. In conclusion, Klotho expression is associated with epithelial ovarian cancer progression, and the protein may serve as an independent marker for ovarian cancer prognosis. Klotho’s role in cancer warrants further elucidation. Overexpression of Klotho suppresses liver cancer progression and induces cell apoptosis by negatively regulating wnt/β-catenin signaling pathway. Klotho: a novel biomarker for cancer. Downregulation of Klotho was found in several cancers, such as pancreatic cancer, HCC, and other tumors. Downregulation of Klotho resulted in promoted proliferation and reduced apoptosis of cancer cells. The relevant mechanisms include the fibroblast growth factor signaling, the insulin-like growth factor 1 receptor pathway, and the Wnt/β-catenin signaling pathway. Furthermore, the Klotho protein hopefully provides new insights into cancer target treatment.. Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinomaThese data suggest that klotho acts as a tumor suppressor and an inhibitor of the Wnt/β-catenin pathway in HCC, and moreover, that soluble klotho is a potential serum biomarker for HCC. Vitamin D: a custodian of cell signaling stability in health and disease.. Vitamin D, reactive oxygen species and calcium signalling in ageing and disease. Vitamin D is a hormone that maintains healthy cells. It functions by regulating the low resting levels of cell signalling components such as Ca(2+) and reactive oxygen species (ROS). Its role in maintaining phenotypic stability of these signalling pathways depends on the ability of vitamin D to control the expression of those components that act to reduce the levels of both Ca(2+) and ROS. This regulatory role of vitamin D is supported by both Klotho and Nrf2. A decline in the vitamin D/Klotho/Nrf2 regulatory network may enhance the ageing process, and this is well illustrated by the age-related decline in cognition in rats that can be reversed by administering vitamin D. A deficiency in vitamin D has also been linked to two of the major diseases in man: heart disease and Alzheimer’s disease). 1,25-Dihydroxyvitamin D3 (1,25D) is the renal metabolite of vitamin D that signals through binding to the nuclear vitamin D receptor (VDR). The ligand-receptor complex transcriptionally regulates genes encoding factors stimulating calcium and phosphate absorption plus bone remodeling, maintaining a skeleton with reduced risk of age-related osteoporotic fractures. 1,25D/VDR signaling exerts feedback control of Ca/PO4 via regulation of FGF23, klotho, and CYP24A1 to prevent age-related, ectopic calcification, fibrosis, and associated pathologies. Vitamin D also elicits xenobiotic detoxification, oxidative stress reduction, neuroprotective functions, antimicrobial defense, immunoregulation, anti-inflammatory/anticancer actions, and cardiovascular benefits. Many of the healthspan advantages conferred by 1,25D are promulgated by its induction of klotho, a renal hormone that is an anti-aging enzyme/coreceptor that protects against skin atrophy, osteopenia, hyperphosphatemia, endothelial dysfunction, cognitive defects, neurodegenerative disorders, and impaired hearing. In addition to the high-affinity 1,25D hormone, low-affinity nutritional VDR ligands including curcumin, polyunsaturated fatty acids, and anthocyanidins initiate VDR signaling, whereas the longevity principles resveratrol and SIRT1 potentiate VDR signaling. 1,25D exerts actions against neural excitotoxicity and induces serotonin mood elevation to support cognitive function and prosocial behavior. Together, 1,25D and klotho maintain the molecular signaling systems that promote growth (p21), development (Wnt), antioxidation (Nrf2/FOXO), and homeostasis (FGF23) in tissues crucial for normal physiology, while simultaneously guarding against malignancy and degeneration. Therefore, liganded-VDR modulates the expression of a “fountain of youth” array of genes, with the klotho target emerging as a major player in the facilitation of health span by delaying the chronic diseases of aging. THE ANTI-AGING PROTEIN KLOTHO ENHANCES OLIGODENDROCYTE MATURATION AND MYELINATION OF THE CENTRAL NERVOUS SYSTEM KLOTHO, A NOVEL REGULATOR OF SOMATOTROPE PROLIFERATION AND HORMONE SECRETION
    Our findings indicate, for the first time, a role for klotho and bFGF in somatotroph proliferation and GH secretion. The aging suppressor Klotho: a potential regulator of growth hormone secretion. Klotho sensitive regulation of dendritic cell functions by vitamin E. The up-regulation of klotho by VitE could contribute to the inhibitory effects of VitE on NF-κB-mediated DC functional maturation. The events might contribute to immunotherapeutic effect of VitE on the pathophysiology of klotho-related disease.
    The Three Sisters of Fate in Multiple Sclerosis: Klotho (Clotho), Fibroblast Growth Factor-23 (Lachesis), and Vitamin D (Atropos). Klotho, which is secreted from Choroid Plexus, could be a response to the inflammatory condition in MS. Elevated FGF-23 levels suppress 1α-hydroxylase and upregulates 24α-hydroxylase, which results in a decrease in 1,25-(OH)2D3 levels. Thus, the neuroprotective and immunomodulatory effects of vitamin D might not be seen in MS patients. FGF-23, Klotho and Vitamin D Levels in Scleroderma.
    The decreased serum Klotho, 25-OH Vit D, and increased iPTH levels in the scleroderma patients may be associated with the pathogenesis of this disease and could be considered a future therapeutic target.

    The levels of Klotho in the brain showed a striking decrease with aging. Studies led to the observation that secretion of Klotho is regulated by insulin. They found that insulin, a hormone usually associated with diabetes, increases significantly the levels of secreted Klotho. The reason this finding is important is because excess insulin has been previously implicated in a biochemical pathway that is associated with a decreased life span and elevated oxidative stress. In addition, this observation provides a potentially pivotal link between Klotho and sugar metabolism, and raises an intriguing relationship between Klotho and type II diabetes, commonly known as late onset diabetes. The authors are proposing a novel mechanism of action for Klotho whereby insulin increases Klotho secretion, i.e., activity, and in turn, the secreted Klotho inhibits insulin’s actions in the cell, which are known to be detrimental when insulin is in excess.

  • carol close

    PubMed shows- Alcohol reduces aldosterone dehydrating you which dehydration shuts off klotho, the anti-aging hormone. PubMed shows these supplements that increase klotho are rhein (found in yellow dock, rhubarb, and Chinese rhubarb), growth hormone, exercise, vitamin D, vitamin E, resveratrol, compound H (C16H22BF4N3 -5-Neopentyl-2-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium tetrafluoroborate), insulin (juniper berries increase insulin), Notopterygium incisum Ting. (I would not recommend this as the plant is now endangered), Semen Raphani  (radish seed), and Epimedium biloba (horny goat weed).

  • lostfalco

    Hey Joe, speaking of insulin…have you looked into intranasal insulin? A number of us are testing it out right now and early results have been very positive for mood and energy levels. Sadly, it has meta-cresol in it but it may be worth finding a work around. Also, most people don’t know that you can buy it legally over the counter without a prescription in the U.S. so it’s readily available.

    1. Joseph M. Cohen


      1. lostfalco

        It’s pretty amazing stuff and the research on humans is quite extensive. My hope is that it can really help many of your clients with depression, insulin resistance, and thyroid issues. The research is going to blow you away. =)

        1. Joseph M. Cohen

          Looks really interesting. Great find!

        2. Joseph M. Cohen

          Any links to products?

          1. lostfalco

            Thanks, man. Novolin R was used in one of the studies. You should be able to buy it without a prescription at Walmart. Just go to the pharmacy and ask them for it. Here is the study that used it.

            “Fasting subjects came on five separate mornings, one to six weeks apart, to receive saline or one of four insulin doses (10, 20, 40, or 60 IU) in randomized counterbalanced order. An initial blood sample was obtained and subjects were placed in a supine position with the head tilted back. One-hundred μL of insulin (Novolin R, Novo Nordisk, Princeton, NJ, USA) or saline were administered with a needle-less syringe into alternating nostrils for a total volume of 600 μL at each visit. One-hundred μL of insulin corresponded to 10 IU; saline was administered as needed at insulin visits to achieve the total study drug volume of 600 μL. Subjects were instructed to sniff following administration to facilitate transport of insulin into the nasal cavity. Subjects rested for 15-minutes. “

            reply icon
  • george

    So basically, we can’t do much about this (yet), except some exercise.

    Very interesting nonetheless.

    1. Joseph M. Cohen

      And also:
      Carbs to increase Insulin
      PPARgamma activators
      Statins/Red yeast rice
      Activated charcoal
      Gentian root extract

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