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Klotho is attracting considerable attention in the ageing research field by its relation with various age-related diseases and frailty. Klotho was identified as a gene associated with ageing and subsequent researches revealed that soluble α-Klotho is an ”anti-ageing hormone” with a wide range of physiological functions, including the regulation of phosphorus and calcium metabolism, antioxidant, anti-inflammatory, anti-fibrotic and neuroprotective effects.

We hosted a seminar on soluble α-Klotho and presented the latest research findings in June 2025. “Diverse Functions of an Anti-Aging Hormone, Klotho”(IBL-America, USA) summarizes a wide range of findings that were introduced in the seminar in an accessible manner, from the basic physiological functions of Klotho to techniques for measuring soluble α-Klotho, its association with age-related diseases as revealed by large-scale cohort studies, and even the relationship between soluble α-Klotho concentrations in the blood and factors such as exercise, diet, medication and senolytics.

Summary

The discovery of Klotho: a turning point in ageing research
The Klotho gene is an ageing-related gene that was discovered in 1997. “klotho” is named after the Greek goddess, Clotho, who spins the thread of life. Mice with defective klotho gene expression exhibited a syndrome that resembles human aging whereby mice aged rapidly and died young. On the other hand, mice overexpressing Klotho have been shown to live longer, indicating that Klotho plays a significant role in the ageing process.

Basic functions of Klotho in the kidneys
α-Klotho is a membrane protein expressed primarily in renal tubular cells, and functions as a co-receptor for FGF23. α-Klotho plays a key role in maintaining the homeostasis of phosphorus and calcium metabolism, inhibiting phosphorus reabsorption in cooperation with FGF23 whilst also regulating the production of active vitamin D. Klotho-deficient mice exhibit hyperphosphatemia, and their aging phenotype is improved by a low-phosphorus diet, suggesting that regulation of phosphorus metabolism by Klotho may be closely linked to the ageing process.

The reason why soluble α-Klotho is known as the ”anti-ageing hormone”
The extracellular domain of the full-length transmembrane α-Klotho is cleaved and released into the blood. Soluble α-Klotho circulates throughout the body and acts on a variety of tissues and organs, which is why it is often referred to as an anti-aging hormone. A sandwich ELISA was developed to quantify soluble a-klotho using small sample volume (1). It has been reported that the blood soluble α-Klotho concentrations decrease with aging. A relation with impaired renal function has also been reported.

Cell protection by Anti-oxidant action
Oxidative stress, which increases with age, is considered to be involved in various aging related diseases, such as atherosclerosis and cardiovascular disease. Klotho suppresses cell damage caused by reactive oxygen species, by activating FoxO and Nrf2 pathways and promoting the expression of antioxidant enzymes such as SOD and HO-1. These effects are considered to be one of the mechanisms to protect cells from oxidative stress

Anti-inflammatory and anti-fibrotic action
Chronic inflammation is considered to be a key driver of ageing. It has been shown that klotho inhibits the activation of NF-κB and reduces the production of inflammatory cytokines such as TNF-α and IL-6. In a COPD in-vitro model, experiments using mouse alveolar macrophages reported that Klotho suppresses the production of inflammatory cytokines induced by tobacco smoke extract. Furthermore, it is thought that Klotho suppresses the differentiation into myofibroblasts and collagen production by inhibiting TGF-β signaling, thereby contributing to the inhibition of the progression of pathological fibrosis observed in the lungs, liver, and kidneys.

Potential for Tumor suppression and Neuroprotective action
Klotho has also been reported to have tumor suppression. Cell proliferation was inhibited in pancreatic cancer cell culture and tumor size was reduced when pancreatic cancer cells were transplanted into mice and administrated with klotho compared to non-klotho administrated control. It is thought that the suppression of IGF and FGF signaling is related.
Neuroprotective action also attracts attention. In a study in which a single dose of recombinant Klotho was administered to elderly Rhesus monkeys with an average age of 21.8 years, cognitive function improvement was observed four hours after administration, and this effect was still evident 14 to 23 days later. The development of gene and cell therapies targeting Klotho is underway, and it is expected to apply in neurodegenerative diseases field.

The clinical significance of Klotho, demonstrated by NHANES study
CDC (US Centers for Disease Control and Prevention) conducted the National Health and Nutrition Examination Survey (NHANES), in which soluble α-Klotho concentrations were measured in over 13,000 serum samples collected between 2007 and 2016. Since then, more than 130 research papers have been published. These studies have shown that low soluble α-Klotho concentration in the blood is associated with elevated inflammation markers, cardiovascular diseases such as heart failure and myocardial infarction (2), osteoarthritis (3), frailty (4), reduced muscle mass (5), and increased mortality risk (6).
Furthermore, the relationship between soluble α-Klotho and “phenotypic age,” which is calculated on the basis of physical function and test results rather than chronological age, is also being investigated. A U-shaped relationship was observed between soluble α-Klotho concentrations and the rate of aging. However, within the range below 1,000 pg/mL, where most participants were distributed, lower soluble α-Klotho concentrations were associated with a faster rate of phenotypic aging (7). Further studies are needed to clarify whether reduced Klotho levels contribute to the onset and progression of disease, or whether disease itself leads to a decline in Klotho levels.

“Negative spiral” by reduction of Klotho
This article introduces the important concept of a “Negative spiral,” in which reduced Klotho levels and age-related diseases mutually reinforce one another. Blood soluble α-Klotho concentrations decrease with aging. Low soluble α-Klotho concentration in the blood is associated with an elevated risk of kidney diseases, diabetes, cardiovascular diseases. These age-related diseases are associated with chronic inflammation and the release of inflammatory cytokines. Inflammatory cytokines suppress Klotho gene expression, further reducing the concentration of soluble α-Klotho in the blood. It has been suggested that this negative spiral may accelerate ageing and shorten lifespan.

Association between Klotho and Lifestyle Factors, Therapeutic Interventions
To address the above-mentioned “Negative spiral,” lifestyle habits and therapeutic interventions research is being conducted. Regarding exercise, an increase in soluble α-Klotho concentrations following a single session of resistance training (8), as well as high concentrations of soluble α-Klotho in athletes (9) have been reported. High anti-inflammatory diet (10), dietary fiber intake (11), and strict adherence to the Mediterranean diet (12) were all associated with high concentrations of soluble α-Klotho. Furthermore, individuals who experienced a significant weight reduction from obese to non-obese, the larger the weight reduction, the higher the klotho levels.
Regarding the effects of drugs, ARBs, including Losartan (13), Fluvastatin and Vitamin D, have been reported to increase Klotho levels. Diabetes treatments such as GLP-1 receptor agonists, DPP-4 inhibitors, metformin and PPAR-γ agonists have also been reported to increase Klotho levels in animal studies (14). Furthermore, senolytics, which remove ageing cells, are also attracting attention. A study using dasatinib in combination with quercetin or fisetin reported to increase Klotho by removal of senescent cells. A human clinical trial involving the administration of dasatinib and quercetin (15) reported increased urinary Klotho levels.

Conclusion
In addition to the mineral metabolic function as a co-receptor for FGF23, klotho has a variety of functions as an anti-aging hormone, including antioxidant, anti-inflammation, fibrosis inhibition, tumor suppressive and neuroprotective effects. Soluble α-Klotho concentrations in blood have been reported to be associated with various age-related diseases, frailty, and mortality, and are attracting attention as biomarkers. Furthermore, various approaches that may increase Klotho levels are researched, including exercise, dietary changes, drug therapy, senolytics and even gene therapy (16).
Extending healthy lifespan has long been a challenge for humankind. Further research and developments by utilizing Klotho are expected.


Please refer to the following publication for more details.

Diverse Functions of an Anti-Aging Hormone, Klotho
（IBL-America, USA）

References
  1 Yamazaki Y et al. Biochem Biophys Res Commun. 2010. PMID: 20599764
  2 Xu JP et al. Front Cardiovasc Med. 2022. PMID: 35795366
  3 Qiu Y et al. PLoS One. 2024. PMID: 39556550
  4 Yuan M et al. Am J Transl Res. 2024. PMID: 39114692
  5 Xie Y et al. Front Nutr. 2024. PMID: 38854159
  6 Sadr N et al. Br J Clin Pharmacol. 2024. PMID: 39165068
  7 Li H et al. BMC Geriatr. 2023. PMID: 38017397
  8 Morishima T and Ochi E. Physiol Rep. 2021. PMID: 34713986
  9 Mostafidi E et al. Nephrourol Mon. 2016. PMID: 26981496
10 Ma TC et al. Front Nutr. 2022. PMID: 35619959
11 Liu S et al. Nutrients. 2023. PMID: 37513564
12 Wu SE et al. Nutrients. 2022. PMID: 36235560
13 Lim SC et al. Renin Angiotensin Aldosterone Syst. 2014. PMID: 23380567
14 Prud'homme GJ et al. Front Aging. 2022. PMID: 35903083
15 Zhu Y et al. EBioMedicine. 2022. PMID: 35292270
16 Castner SA et al. Nat Aging. 2023. PMID: 37400721

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