Klotho
Klotho is a transmembrane and circulating protein that plays a key role in aging and longevity. It functions as a co-receptor for fibroblast growth factor 23 (FGF23), regulating phosphate and calcium metabolism, but it also has independent antioxidant, anti-inflammatory, and neuroprotective effects. Higher levels of klotho are associated with extended lifespan, enhanced cognitive function, and reduced age-related degeneration, while its decline with age contributes to oxidative stress, inflammation, and tissue damage. Researchers are exploring ways to boost klotho expression as a potential anti-aging strategy.
"The year 2017 marked the 20th anniversary of the first publication describing Klotho. This single protein was and is remarkable in that its absence in mice conferred an accelerated aging, or progeroid, phenotype with a dramatically shortened life span. On the other hand, genetic overexpression extended both health span and life span by an impressive 30%. Not only has Klotho deficiency been linked to a number of debilitating age-related illnesses but many subsequent reports have lent credence to the idea that Klotho can compress the period of morbidity and extend the life span of both model organisms and humans. This suggests that Klotho functions as an integrator of organ systems, making it both a promising tool for advancing our understanding of the biology of aging and an intriguing target for interventional studies. In this review, we highlight advances in our understanding of Klotho as well as key challenges that have somewhat limited our view, and thus translational potential, of this potent protein."
On Saturday, February 1, 2025, I presented the information on this page in a live webinar. Click above to view!
Klotho as it Relates to Our Health
1. Brain Health & Cognitive Function
Brain Health & Cognitive Function
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Low Klotho: Linked to neurodegeneration, Alzheimer’s, and cognitive decline. Reduced levels contribute to oxidative stress, neuroinflammation, and impaired synaptic plasticity.
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Increased Klotho: Improves memory, enhances cognitive resilience, and offers neuroprotection against conditions like Alzheimer's and Parkinson’s. Even in people with genetic risk factors, higher klotho levels correlate with better brain function.
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Study: Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations
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Findings: Klotho deficiency is associated with cognitive impairment and the development of age-related diseases. Serum klotho levels decline with advanced age and conditions like chronic kidney disease, highlighting its potential diagnostic significance.
2. Cardiovascular Health
Cardiovascular Health
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Low Klotho: Increases arterial stiffness, raises the risk of hypertension, and accelerates atherosclerosis. It also disrupts calcium metabolism, leading to vascular calcification.
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Increased Klotho: Enhances endothelial function, reduces inflammation, and protects against heart disease, hypertension, and stroke. It also improves circulation by regulating nitric oxide production.
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Study: Implications of Klotho in Vascular Health and Disease
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Findings: Klotho improves endothelial dysfunction by promoting nitric oxide production and mediates anti-inflammatory and anti-aging effects, such as suppression of adhesion molecule expression and inhibition of Wnt signaling. It also attenuates vascular calcification and prevents cardiac hypertrophy.
3. Kidney Function & Detoxification
Kidney Function & Detoxification
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Low Klotho: Strongly linked to chronic kidney disease (CKD) and renal fibrosis. Kidney dysfunction can further reduce klotho, creating a vicious cycle.
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Increased Klotho: Supports kidney function, protects against fibrosis, and helps regulate phosphate metabolism to prevent damage.
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Study: Klotho in Health and Disease
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Findings: Secreted klotho functions as a humoral factor that inhibits acute kidney injury, vascular calcification, renal fibrosis, and cancer metastasis in an FGF23-independent manner. Klotho deficiency induces resistance to FGF23 and predisposition to phosphate retention, a critical feature in the pathophysiology of chronic kidney disease.
4. Bone & Joint Health
Bone & Joint Health
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Low Klotho: Disrupts calcium-phosphorus balance, increasing the risk of osteoporosis and joint degeneration. Also linked to arthritis and skeletal fragility.
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Increased Klotho: Promotes bone strength and density, reduces inflammation, and may help in conditions like osteoarthritis and rheumatoid arthritis.
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Findings: Klotho proteins are essential components of endocrine fibroblast growth factor receptor complexes, governing multiple metabolic processes, including mineral metabolism. FGF23, secreted by osteocytes, binds to αKlotho-FGFR complexes in renal tubules to regulate mineral metabolism, impacting bone health.
5. Immune Function & Activation
Immune Function & Inflammation
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Low Klotho: Increases chronic inflammation (inflammaging), contributes to autoimmune disorders, and weakens immune response to infections.
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Increased Klotho: Acts as an anti-inflammatory and immunomodulatory factor, improving immune resilience and reducing excessive immune activation.
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Study: Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations
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Findings: Klotho inhibits pathways linked to aging, such as TGF-β, IGF-1, Wnt, and NF-κB, which can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis, and neoplasia. It also increases cell-protective antioxidant enzymes through Nrf2 and FoxO, modulating immune responses.
6. Metabolic Health & Insulin Sensitivity
Metabolic Health & Insulin Sensitivity
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Low Klotho: Associated with insulin resistance, metabolic syndrome, and type 2 diabetes.
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Increased Klotho: Improves glucose metabolism, enhances insulin sensitivity, and may help prevent metabolic disorders.
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Study: Association Between Soluble α-Klotho Protein and Metabolic Syndrome in Adults
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Findings: Soluble klotho protein concentration is inversely correlated with the presence of metabolic syndrome and its components, such as abdominal obesity and high triglyceride levels. Klotho may act on multiple signaling pathways in different organs and tissues, playing roles in anti-aging and protection from metabolic syndrome.
7. Skin Health & Aging
Skin Health & Aging
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Low Klotho: Contributes to premature skin aging, loss of elasticity, and impaired wound healing.
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Increased Klotho: May enhance skin regeneration, protect against oxidative damage, and support collagen production.
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Study: Klotho: A Potential Therapeutic Target in Aging and Neurodegenerative Diseases
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Findings: Klotho deficiency is associated with reduced growth and diminished longevity, which can manifest in skin aging. Enhancing klotho levels could offer therapeutic benefits in mitigating age-related skin changes.
8. Lung Health
Lung Health
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Low Klotho: Correlated with pulmonary fibrosis, COPD, and other chronic lung diseases.
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Increased Klotho: May protect against lung inflammation and improve respiratory function.
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Study: Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations
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Findings: Klotho inhibits pathways such as TGF-β and NF-κB, which are involved in inflammation and fibrosis. By modulating these pathways, klotho may protect against lung diseases characterized by inflammation and fibrosis.
9. Cancer
Cancer Risk
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Low Klotho: Allows for increased cellular stress and uncontrolled cell proliferation, potentially raising cancer risk.
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Increased Klotho: Functions as a tumor suppressor, reducing oxidative stress and inhibiting cancer cell growth.
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Study: Klotho in Health and Disease
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Findings: Secreted klotho inhibits cancer metastasis in an FGF23-independent manner. Various factors that affect klotho expression have been identified, suggesting that prevention of klotho decline and supplementation can be novel therapeutic strategies for age-related diseases, including cancer.
10. Lifespan & Overall Longevity
Lifespan & Overall Longevity
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Low Klotho: Accelerates aging, increases susceptibility to age-related diseases, and reduces overall lifespan.
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Increased Klotho: Extends lifespan in animal studies, delays aging processes, and enhances resilience to age-related decline.
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Findings: The FGF-Klotho endocrine system has a crucial role in the pathophysiology of aging-related disorders, including diabetes, cancer, arteriosclerosis, and chronic kidney disease. Targeting the FGF-Klotho endocrine axes might have therapeutic benefits in multiple systems, potentially influencing lifespan and longevity.
