Klotho: Role in Human Health and Disease
Overview and Fundamental Biology
Klotho is an anti-aging protein that functions as an essential cofactor for FGF23 signaling and serves as a humoral factor regulating phosphate metabolism, oxidative stress, and cellular senescence. 1
Klotho exists in three distinct forms with separate biological functions 2:
- Membrane-bound Klotho: Acts as an obligatory co-receptor for FGF23 at the FGF23 receptor complex, enabling FGF23 signaling in target tissues 1
- Soluble/secreted Klotho: Released into circulation through shedding of the extracellular domain; functions as a humoral factor with pleiotropic activities 2, 3
- Intracellular Klotho: Suppresses inflammation-mediated cellular senescence 2
Primary Physiological Functions
Mineral Metabolism Regulation
Klotho is essential for FGF23-mediated phosphate homeostasis. FGF23 binds to the FGF23 receptor/Klotho complex in the kidney, which increases phosphate excretion into urine and decreases 1,25-dihydroxyvitamin D production by inhibiting CYP27B1 1. This mechanism prevents hyperphosphatemia and regulates calcium-phosphate balance 3.
The membrane-bound form specifically maintains kidney homeostasis by 4:
- Regulating FGF23 signaling pathways
- Modulating vitamin D metabolism
- Controlling phosphate balance through renal ion transport
Anti-Aging and Cellular Protection
Klotho deficiency accelerates aging phenotypes, while overexpression extends lifespan in animal models. 2, 3 The protein exerts multiple protective mechanisms 4, 5:
- Anti-oxidative effects: Reduces oxidative stress at the cellular level
- Anti-inflammatory actions: Suppresses inflammation-mediated cellular senescence
- Anti-fibrotic properties: Prevents tissue fibrosis in multiple organs
- Tumor suppression: Modulates key signaling pathways including Wnt/β-catenin, IGF-1, PI3K/AKT, and TGF-β 5
Clinical Significance in Disease States
Chronic Kidney Disease
Klotho deficiency is strongly associated with CKD progression and represents a critical therapeutic target. 4 The 2025 KDIGO guidelines acknowledge that the clinical relevance and applicability of measuring Klotho remains a knowledge gap requiring further research 1.
In CKD, Klotho deficiency contributes to 4:
- Diabetic kidney disease progression through increased inflammation, oxidative stress, and fibrosis
- Reduced protection against various kidney pathological phenotypes
- Mineral bone disorder complications
Circulating soluble Klotho levels decrease with declining kidney function and advancing age. 2, 6
Cardiovascular Disease
Klotho deficiency is linked to 4, 3:
- Enhanced development of arteriosclerosis
- Ectopic vascular calcification
- Increased cardiovascular mortality risk
Neurodegeneration and Cognitive Function
Klotho deficiency is associated with cognitive impairment and accelerated neurodegeneration. 6 The protein plays a protective role in 6:
- Preventing age-related cognitive decline
- Reducing risk of neurodegenerative disorders
- Maintaining neuronal health through anti-oxidative mechanisms
Other Disease Associations
Klotho deficiency contributes to 4, 5, 3:
- Various cancers (through loss of tumor-suppressive function)
- Alzheimer's disease
- Inflammatory bowel disease
- Liver disease
- Osteoporosis and bone metabolism disorders
Tissue Distribution and Detection
Klotho is predominantly expressed in the kidney, with secondary expression in the brain and pancreas. 4, 3 Soluble Klotho can be detected on urinary extracellular vesicles using super-resolution microscopy techniques 1.
Clinical Measurement Considerations
The 2025 KDIGO guidelines identify measuring Klotho as a research priority but acknowledge that clinical applicability remains undefined. 1 Current knowledge gaps include:
- Optimal methods for Klotho measurement in clinical practice
- Whether Klotho levels translate to improved clinical outcomes
- Standardization of assays across laboratories
Therapeutic Implications
Exogenous Klotho supplementation represents a promising therapeutic strategy for multiple diseases, particularly diabetic kidney disease. 4 Potential interventions include 4, 5:
- Direct Klotho protein supplementation
- Gene therapy approaches to increase Klotho expression
- Medications that upregulate endogenous Klotho production
- Natural strategies including exercise and dietary interventions to overcome Klotho deficiency
Multiple medications have been demonstrated to influence Klotho levels, though specific clinical protocols remain under investigation. 6
Key Clinical Pitfalls
The primary limitation is that Klotho measurement is not yet standardized for routine clinical use despite strong biological rationale. 1 Clinicians should recognize that:
- Klotho levels decline with age and CKD progression, but specific treatment thresholds are not established 2, 6
- The relationship between measured Klotho levels and clinical outcomes requires validation in large trials 1
- Different forms of Klotho (membrane vs. soluble) have distinct functions that may not be captured by single measurements 2, 3