Klotho interactions with Vitamin D

Klotho interactions with Vitamin D Perplexity AI - Deep Research
How individuals can increase Klotho protein levels Perplexity AI
Klotho antiaging protein: molecular mechanisms and therapeutic potential in diseases - March 2025
- Some Klotho and Vitamin D studies from Google Scholar

Klotho interactions with Vitamin D Perplexity AI - Deep Research

Klotho, Vitamin D, and Their Impact on Health: A Comprehensive Review

Klotho and vitamin D have emerged as critical players in mineral homeostasis, aging processes, and various health conditions. Their intricate relationship represents a fascinating area of research with significant implications for understanding age-related diseases and developing novel therapeutic approaches. This review explores the biology of Klotho, its relationship with vitamin D metabolism, and how imbalances in this system affect human health.

Discovery and Function of Klotho

Klotho was first identified in 1997 as a gene related to aging when researchers discovered that mice lacking this gene exhibited a syndrome resembling human premature aging. Conversely, overexpression of Klotho extended both health span and life span by an impressive 30% in laboratory models 14. The Klotho gene encodes a novel type I membrane protein belonging to the β-glycosidase family, primarily expressed in distal tubule cells of the kidney and the choroid plexus in the brain 1 4.
Functionally, Klotho exists in two main forms: membrane-bound and secreted. The membrane-bound form serves as a co-receptor for fibroblast growth factor 23 (FGF23), playing a crucial role in phosphate and calcium homeostasis 3. The secreted form, which results from ectodomain shedding of the membrane protein, functions as a humoral factor that inhibits acute kidney injury (AKI), vascular calcification, renal fibrosis, and cancer metastasis in an FGF23-independent manner 5.
Recent studies have revealed that Klotho levels decline with age, beginning as early as the fifth decade of life, potentially before the onset of age-related impairments in physical function 13. This decline has been associated with increased mortality risk, with research showing that low serum Klotho concentration (<666 pg/mL) correlates with a 31% higher risk of death compared to higher Klotho levels (>985 pg/mL) 11.

The Klotho-Vitamin D Regulatory Axis

One of Klotho's most significant roles is its participation in a regulatory circuit involving vitamin D metabolism. This relationship is bidirectional and finely balanced:

Vitamin D Regulation of Klotho

The vitamin D receptor (VDR) directly regulates Klotho gene expression. Multiple vitamin D responsive elements (VDREs) control Klotho expression, with the most active elements located at considerable distances (-31 kb to -46 kb) from the Klotho transcriptional start site 7 10. Research has demonstrated that administration of 1,25-dihydroxyvitamin D3 (the active form of vitamin D) induces Klotho expression in the kidney 1 4.

Klotho Regulation of Vitamin D

Conversely, Klotho functions in a negative regulatory circuit of the vitamin D endocrine system through regulation of 1α-hydroxylase gene expression 1 4. This enzyme is responsible for converting 25-hydroxyvitamin D to the active 1,25-dihydroxyvitamin D. By helping to control vitamin D activation, Klotho plays a crucial role in preventing vitamin D toxicity.
Together with FGF23, Klotho forms part of a bone-kidney axis that not only regulates phosphate levels to prevent ectopic calcification but also governs vitamin D bioactivation and catabolism 15. This system is crucial for maintaining mineral homeostasis and may have broader implications for healthful aging by reducing the risk of chronic diseases.

Health Implications of Klotho Deficiency

The consequences of Klotho deficiency are far-reaching and have been extensively studied in animal models and human observational studies.

Mineral Metabolism Disturbances

In Klotho-deficient mice, researchers observed elevated levels of serum calcium (10.9 ± 0.31 mg/dl vs. 10.0 ± 0.048 mg/dl in wild-type), phosphorus (14.7 ± 1.1 mg/dl vs. 9.7 ± 1.5 mg/dl in wild-type), and most notably, 1,25-(OH)2D (403 ± 99.7 mg/dl vs. 88.0 ± 34.0 mg/dl in wild-type) 1 4. This pattern suggests that Klotho deficiency leads to dysregulation of vitamin D metabolism and mineral homeostasis.

Accelerated Aging Phenotype

The most striking consequence of Klotho deficiency is an accelerated aging phenotype. Klotho-null mice exhibit shortened lifespan, multiple organ degeneration, vascular calcification, cardiovascular disease, and frailty 9 14. This premature aging syndrome includes features such as:

Growth retardation
Decreased bone mineral density
Ectopic calcification
Skin atrophy
Pulmonary emphysema
Cognitive impairment
Sarcopenia (muscle wasting)

Interestingly, many of these aging-like phenotypes can be alleviated by reducing serum 1,25-(OH)2D concentrations through dietary restriction, suggesting that elevated vitamin D levels may contribute to the accelerated aging phenotype in Klotho-deficient models 1 3 4.

Neurological Implications

Klotho deficiency has been associated with cognitive impairment and neurodegenerative processes. Research indicates that Klotho could play a protective role against neurodegeneration, making it a potential therapeutic target for conditions such as Alzheimer's disease and other age-related cognitive disorders 9.

Vitamin D Toxicity and Its Relationship with Klotho

While vitamin D is essential for numerous physiological processes, excessive levels can lead to toxicity (hypervitaminosis D). The primary concern with vitamin D toxicity is hypercalcemia, which can cause:

Gastrointestinal symptoms such as upset stomach and vomiting
Weakness and fatigue
Frequent urination
Bone pain
Kidney troubles, including kidney stones 2

The relationship between vitamin D toxicity and Klotho is complex. Recent research suggests that vitamin D-associated mortality risk is observed only with concurrently decreasing Klotho levels, indicating that vitamin D metabolism dysfunction, rather than simply elevated vitamin D levels, increases mortality risk 6 12. This finding has important implications for vitamin D supplementation therapy, suggesting that Klotho levels could help guide treatment decisions in populations with vitamin D deficiency 6.

The FGF23-Klotho-Vitamin D Axis in Disease

The interconnected system of FGF23, Klotho, and vitamin D plays a crucial role in various pathological conditions:

Chronic Kidney Disease (CKD)

In CKD, Klotho levels decline progressively, contributing to the development of mineral and bone disorders. This decline leads to resistance to FGF23 and predisposition to phosphate retention, representing a critical feature of CKD pathophysiology 5. The dysregulation of the FGF23-Klotho-vitamin D axis in CKD contributes to secondary hyperparathyroidism, vascular calcification, and increased cardiovascular mortality.

Cardiovascular Disease

Klotho deficiency has been linked to accelerated vascular calcification and atherosclerosis. The combination of decreasing serum 25-hydroxyvitamin D (<50 nmol/L) and Klotho (<848.4 pg/mL) was associated with significant

all-cause mortality (HR, 1.48) and
cardiovascular disease mortality (HR, 2.36) 6,

highlighting the importance of this regulatory axis in cardiovascular health.

Aging and Longevity

The role of Klotho as an aging-suppressor gene has significant implications for human longevity. Klotho variants have been associated with various age-related conditions affecting bone mineral density, osteoarthritis, systolic blood pressure, and longevity 14. Understanding how to maintain or restore adequate Klotho levels with aging could potentially extend healthspan and reduce the burden of age-related diseases.

Potential Therapeutic Applications

Given the profound effects of Klotho on multiple physiological systems, various therapeutic strategies targeting the Klotho-vitamin D axis are being explored:

Klotho Supplementation

Prevention of Klotho decline and supplementation of Klotho has been proposed as a novel therapeutic strategy for many age-related diseases 5. This approach could potentially address conditions ranging from kidney disease and cardiovascular complications to neurodegenerative disorders.

Vitamin D Management

Understanding the interplay between Klotho and vitamin D could help optimize vitamin D supplementation strategies. Measuring Klotho levels might help predict long-term mortality outcomes and guide vitamin D supplementation therapy decision-making, especially in populations with vitamin D deficiency 6 12.

Lifestyle Interventions

Emerging evidence suggests that physical activity and certain dietary patterns might influence Klotho expression. These modifiable factors could potentially be leveraged to maintain optimal Klotho levels throughout aging 13.

Conclusion

The intricate relationship between Klotho and vitamin D represents a critical regulatory system with profound implications for human health and aging. Klotho functions as both a regulator of vitamin D metabolism and a downstream target of vitamin D action, creating a feedback loop that maintains mineral homeostasis and may influence the aging process.
The discovery that Klotho deficiency accelerates aging while its overexpression extends lifespan has sparked considerable interest in this protein as a potential therapeutic target. Furthermore, the finding that Klotho levels modify the association between vitamin D and mortality risk underscores the importance of considering both factors when addressing vitamin D deficiency.
As research in this field continues to evolve, a deeper understanding of the Klotho-vitamin D regulatory axis could lead to novel interventions for preventing and treating age-related diseases, ultimately contributing to healthier aging and improved longevity.

Citations:

How individuals can increase Klotho protein levels Perplexity AI

Dietary Interventions

Whole-Diet Approaches

High-quality diets: Higher Healthy Eating Index-2015 scores correlate with increased plasma Klotho levels (40–79 year olds) 1
Antioxidant-rich diets: Higher Composite Dietary Antioxidant Index (vitamins A/C/E, zinc, selenium) associates with elevated Klotho (middle-aged nonsmokers) 1 5
Calorie restriction: Low-calorie, high-protein diets ↑ Klotho in animal brains 1 5
Phosphate management: Restricted phosphate diets improve kidney Klotho expression 1 5

Key Nutrients & Supplements

Intervention	Mechanism	EvidenceNotes
Vitamin D	Binds VDREs in Klotho promoter (mouse/human) 1 5	Food/sun exposure preferred; supplements ineffective in humans 3
Curcumin	↑ Klotho via TGF-β suppression (human kidney cells) 1 5	500–1000 mg/day typical dose
Resveratrol	Induces Klotho expression (animal models) 1	Found in grapes, berries
Ginseng	Upregulates Klotho (preclinical) 1	Traditional dosing: 200–400 mg/day

Note: The above 3 all increase activation of the Vitamin D receptor

Physical Activity

Exercise Protocols

Aerobic training: 12-24 weeks of cycling/running ↑ Klotho (SMD = +0.92) 2
Resistance training: Weightlifting shows strongest effect (SMD = +1.93) 2
Optimal dose: ~150 mins/week demonstrates peak response 2

Key Considerations:

Intensity matters: Moderate exercise ↑ Klotho, while extreme exertion ↓ levels temporarily 1 7
Age effects: Younger adults (<40) show greater exercise-induced ↑ vs older adults 3
Consistency: 16-week programs needed for sustained increases 3

Lifestyle & Pharmacological Options

Evidence-Based Strategies

Probiotics: L. acidophilus + L. lactis ↑ Klotho in aging mice 3 5
ACE inhibitors: Ramipril ↑ Klotho stability (CKD models) 3
Statins: Atorvastatin ↑ Klotho expression (preclinical) 3

Experimental Approaches:

Zinc finger proteins: Artificial transcription factors ↑ Klotho 5-10x in cell models 4
Gene therapy: Early-stage research using viral vectors (animal studies) 6

Key Limitations & Cautions

Human data remains limited – most evidence from animal/cell studies
Vitamin D supplements paradoxically ↓ Klotho in dialysis patients 3
Extreme exercise induces transient ↓ Klotho (military/heat stress) 2 7
No FDA-approved Klotho-boosting drugs currently exist

Practical Recommendation: Combine regular moderate exercise (150 mins/week aerobic + resistance training) with a Mediterranean-style diet rich in antioxidants and polyphenols. Monitor vitamin D status through sunlight/safe exposure rather than high-dose supplements. Consult healthcare providers before trying pharmacological options.

Citations:

Klotho antiaging protein: molecular mechanisms and therapeutic potential in diseases - March 2025

Molecular Biomedicine Volume 6, article number 19, (2025)
Aditya Dipakrao Hajare, Neha Dagar & Anil Bhanudas Gaikwad

Klotho, initially introduced as an anti-aging protein, is expressed in the brain, pancreas, and most prominently in the kidney. The two forms of Klotho (membrane-bound and soluble form) have diverse pharmacological functions such as anti-inflammatory, anti-oxidative, anti-fibrotic, tumour-suppressive etc. The membrane-bound form plays a pivotal role in maintaining kidney homeostasis by regulating fibroblast growth factor 23 (FGF 23) signalling, vitamin D metabolism and phosphate balance. Klotho deficiency has been linked with significantly reduced protection against various kidney pathological phenotypes, including diabetic kidney disease (DKD), which is a major cause of chronic kidney disease leading to end-stage kidney disease. Owing to the pleiotropic actions of klotho, it has shown beneficial effects in DKD by tackling the complex pathophysiology and reducing kidney inflammation, oxidative stress, as well as fibrosis.
Moreover, the protective effect of klotho extends beyond DKD in other pathological conditions, including

cardiovascular diseases,
alzheimer's disease,
cancer,
inflammatory bowel disease, and
liver disease.

Therefore, this review summarizes the relationship between Klotho expression and various diseases with a special emphasis on DKD, the distinct mechanisms and the potential of exogenous Klotho supplementation as a therapeutic strategy. Future research into exogenous Klotho could unravel novel treatment avenues for DKD and other diseases.
Download the PDF from VitaminDWiki

Some Klotho and Vitamin D studies from Google Scholar

Vitamin D Actions: The Lung Is a Major Target for Vitamin D, FGF23, and Klotho;
- JBMR Plus, Volume 5, Issue 12, 1 Dec 2021, e10569, https://doi.org/10.1002/jbm4.10569

Serum Klotho Modifies the Associations of 25-Hydroxy Vitamin D With All-Cause and Cardiovascular Mortality
- The Journal of Clinical Endocrinology & Metabolism, February 2024, https://doi.org/10.1210/clinem/dgad480

Klotho interactions with Vitamin D