The Klotho gene was first identified in mice as a potential aging-suppressor gene. Overexpression of this gene extended lifespan, while disruption led to premature aging. It was later discovered that the Klotho family of membrane proteins act as essential co-receptors for endocrine fibroblast growth factors (FGFs), which regulate various metabolic processes. This review highlights the Klotho-FGF23 endocrine system's role in maintaining phosphate (Pi) homeostasis and explores how Klotho deficiency may contribute to acute kidney injury (AKI), chronic kidney diseases (CKD), and cancer.
Recent findings reveal that Klotho functions as a receptor for the phosphaturic hormone FGF23. A deficiency in Klotho leads to resistance to FGF23 and a predisposition to Pi retention, a key aspect of CKD pathophysiology. The extracellular domain of the Klotho protein undergoes ectodomain shedding and is released into the blood and urine. Secreted Klotho acts as a humoral factor, inhibiting AKI, vascular calcification, renal fibrosis, and cancer metastasis independently of FGF23.
In summary, several factors influencing Klotho expression have been identified. Preventing the decline of Klotho and supplementing it may offer a new therapeutic approach for many age-related diseases.
Low Klotho levels are implicated in a wide range of diseases affecting multiple organ systems.
In chronic kidney diseases (CKD), Klotho deficiency leads to phosphate retention and vascular calcification, exacerbating the progression of CKD and increasing cardiovascular risk.
Cardiovascular diseases related to low Klotho levels include hypertension, atherosclerosis, and heart failure, due to its role in regulating calcium and phosphate metabolism and protecting against vascular calcification. This accelerates the progression of cardiovascular diseases and increases the risk of heart attacks and strokes.
In the respiratory system, low Klotho levels are linked to pulmonary fibrosis and reduced lung function, as Klotho's anti-inflammatory and antifibrotic properties are crucial for maintaining healthy lung tissue.
Cognitive impairments and neurodegenerative diseases, such as Alzheimer's diseases, are also associated with reduced Klotho, as it has neuroprotective properties that support cognitive function.
Klotho plays a significant role in diabetes by influencing insulin sensitivity and glucose metabolism. It enhances insulin signalling pathways, thereby improving the body's ability to regulate blood sugar levels. Low Klotho levels are associated with insulin resistance, a key feature of type 2 diabetes, and can exacerbate hyperglycaemia.
Eye diseases like age-related macular degeneration and cataracts have been linked to decreased Klotho, which is thought to influence oxidative stress and inflammation in ocular tissues.
In the reproductive system, Klotho deficiency can impact fertility and has been connected to conditions such as polycystic ovary syndrome (PCOS).
Furthermore, low Klotho levels are associated with various cancers, promoting tumor growth, metastasis, and reducing the body's ability to inhibit cancer progression.
Overall, Klotho is crucial for maintaining homeostasis across numerous systems, and its deficiency contributes to a broad spectrum of pathological conditions.
Klotho and its mimetics represent a promising therapeutic avenue for various age-related diseases. Klotho mimetics are compounds designed to replicate the beneficial effects of the Klotho protein, potentially offering similar protective and regenerative benefits.
These mimetics aim to enhance Klotho activity, thereby improving insulin sensitivity, reducing oxidative stress, and mitigating inflammation. They hold potential for treating conditions such as chronic kidney diseases, cardiovascular diseases, neurodegenerative disorders, and diabetes.
Current research on Klotho mimetics holds significant promise for developing novel treatments for age related disorders. While much of the work is in preclinical stages, early results are encouraging, paving the way for more extensive human trials and potential clinical applications in the future.
https://www.frontiersin.org/journals/aging/articles/10.3389/fragi.2022.931331/full
KLOTHO: THE SECRET TO LONGEVITY, ANTI-AGING, AND TRANSFORMATIVE HEALTH.
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