FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, September 11, 2024

Understanding and Addressing Vitamin D Resistance:
A Comprehensive Approach Integrating Genetic, Environmental, and Nutritional Factors

Richard Z. Cheng, M.D., Ph.D.

Abstract

Vitamin D resistance, a condition where the body inadequately responds to vitamin D, can manifest in both hereditary and acquired forms. This paper examines the complexities of vitamin D resistance, highlighting the multifactorial nature of the condition, which involves genetic predispositions, lifestyle factors, infections, hormonal imbalances, and micronutrient deficiencies. Hereditary forms, though rare, typically involve mutations in the vitamin D receptor (VDR), while acquired resistance is increasingly common and often associated with chronic illnesses and environmental factors.

The paper underscores the importance of understanding these diverse contributing factors to effectively address vitamin D resistance. The concept of whole-cell nutrition, which emphasizes the synergy between various nutrients, is presented as a crucial approach to mitigating vitamin D resistance. Furthermore, the paper advocates for integrative orthomolecular medicine, which optimizes health through precise nutrient balance, lifestyle modifications, detoxification, and advanced treatments such as bioidentical hormonal balance, photo-biomodulation therapy and stem cell transplantation. Through a holistic and integrative approach, it is possible to enhance the body's ability to utilize vitamin D effectively, leading to improved health outcomes in conditions ranging from osteoporosis to autoimmune diseases.

1. Introduction

Vitamin D is essential for numerous biological functions, including calcium homeostasis, bone health, immune function, and cellular regulation. However, some individuals experience vitamin D resistance, where the body fails to respond adequately to normal or even elevated levels of vitamin D. This resistance can be categorized into two primary forms: hereditary and acquired. Understanding the underlying mechanisms and contributing factors is crucial for effective diagnosis and treatment.

2. Vitamin D Resistance, hereditary and acquired

While hereditary forms of vitamin D resistance, such as those caused by mutations in the vitamin D receptor (VDR), are rare, acquired vitamin D resistance is increasingly recognized and can be more common. This acquired form of resistance is often linked to chronic health conditions, lifestyle factors, and immune system dysregulation. Research suggests that a significant portion of individuals might not respond adequately to standard doses of vitamin D supplementation. Studies have shown that about 25% of individuals may be "low responders" to vitamin D, requiring higher or more individualized doses to achieve the desired physiological effects (1).

2.1 Hereditary Vitamin D Resistance

2.2 Acquired Vitamin D Resistance

Acquired vitamin D resistance occurs later in life and is not caused by genetic mutations. Instead, it results from a variety of external and internal factors that impair the body's ability to utilize vitamin D effectively. This form of resistance is often associated with chronic illnesses, certain medications, or conditions that affect vitamin D metabolism. Recent research indicates that lifestyle factors including diet, sleep, exercise, toxins, nutrition and even hormonal imbalance can all contribute to vitamin D resistance. Examples of acquired vitamin D resistance include chronic kidney disease, which impairs the conversion of vitamin D to its active form, and certain autoimmune conditions, where inflammation and immune dysregulation can alter vitamin D metabolism and receptor function.

2.3 Diagnosis of Vitamin D Resistance

Vitamin D resistance is a diagnosis of exclusion and involves a combination of clinical assessment, laboratory tests (including serum levels of 25(OH)D and PTH) and monitoring the response to vitamin D supplementation. Elevated PTH levels in conjunction with sufficient vitamin D status are particularly indicative of resistance (1).

• Clinical Symptoms: Patients may present with symptoms indicative of vitamin D deficiency or resistance, such as bone pain, muscle weakness, or signs of rickets or osteomalacia.
• Medical History: A comprehensive medical history should include an evaluation of dietary vitamin D intake, sun exposure, and any chronic illnesses such as oral/dental infections, chronic kidney disease or gastrointestinal disorders. Other lifestyle factors that may adversely affect vitamin D metabolism should also be considered.
• Serum 25-Hydroxyvitamin D (25(OH)D) Levels: Measure serum levels of 25(OH)D to determine vitamin D status. Low levels may indicate deficiency, but not necessarily resistance.
• Parathyroid Hormone (PTH) Levels: Elevated PTH levels despite adequate or high levels of 25(OH)D are a hallmark of acquired vitamin D resistance. This suggests that the body is not responding appropriately to vitamin D, leading to secondary hyperparathyroidism (1).
• Calcium and Phosphate Levels: Assess serum calcium and phosphate levels. In cases of vitamin D resistance, calcium absorption may be impaired, leading to hypocalcemia and altered phosphate metabolism (8,9). Corrected calcium has been used when low albumin is present. However, some authors argue against this practice (10).
• Vitamin D Receptor (VDR) Functionality: In some cases, genetic testing for polymorphisms in the vitamin D receptor or related genes may be indicated to assess potential hereditary factors contributing to resistance.
• Vitamin D Supplementation Trials: Administering high doses of vitamin D (e.g., as per the Coimbra protocol) and monitoring changes in serum 25(OH)D and PTH levels can help assess the body's responsiveness. A lack of expected response may indicate resistance (1).
• Longitudinal Monitoring: Regular follow-up with repeat testing can help determine if the patient is a low responder to vitamin D therapy, which may require higher doses for therapeutic effects.

3. Factors Contributing to Vitamin D Resistance

3.1 Genetic Factors

In addition to HVDRR, several genetic polymorphisms significantly influence vitamin D metabolism and receptor function, contributing to variations in vitamin D resistance.

• CYP24A1 Variants: The gene CYP24A1 encodes an enzyme that degrades active vitamin D. Polymorphisms in this gene can lead to lower circulating levels of vitamin D and reduced effectiveness. Variants such as rs3886163 have been associated with decreased vitamin D levels, impacting overall vitamin D metabolism and related health outcomes (11,12).
• CYP2R1 Polymorphisms: The CYP2R1 gene is crucial for converting vitamin D into its active form. Variants in this gene, including rs10500804 and rs12794714, have been linked to lower serum levels of 25-hydroxyvitamin D (25(OH)D), indicating a significant role in vitamin D metabolism (12,13).
• Vitamin D Receptor (VDR) Polymorphisms: The VDR gene, which encodes the vitamin D receptor, also exhibits polymorphisms that can affect vitamin D signaling. Variants such as Fok1 and others in the 3′ UTR region may alter VDR expression and function, thereby influencing vitamin D's biological effects (11,14).
• Impact on Health: Genetic variations in these pathways have been associated with various health conditions, including obesity and type 2 diabetes. Studies highlight the importance of these polymorphisms in understanding vitamin D deficiency and its broader implications for metabolic diseases (13,14).

3.2 Infections

Infections, particularly chronic ones, can contribute to vitamin D resistance. Dental infections, including those related to root canal-treated teeth (15,16), have been implicated in systemic inflammation that can alter vitamin D metabolism. Additionally, infections such as tuberculosis and chronic viral infections can interfere with VDR function and immune regulation, exacerbating vitamin D resistance (1,17-23).

3.3 Physiological Conditions

Obesity is a well-known factor contributing to vitamin D resistance. In obese individuals, vitamin D is sequestered in adipose tissue, reducing its bioavailability. This leads to lower circulating levels of vitamin D and an increased requirement for supplementation (24-26).

3.4 Prescription Drugs

Several prescription drugs can contribute to vitamin D resistance by either increasing the metabolism of vitamin D or interfering with its absorption.

• Antiepileptic Drugs (AEDs)
  • Phenytoin: This drug is known to induce cytochrome P450 enzymes, which accelerate the breakdown of vitamin D, leading to lower levels in the body (27,28).
  • Carbamazepine: Similar to phenytoin, carbamazepine increases the hepatic metabolism of vitamin D, resulting in deficiencies over time (27-29).
  • Phenobarbital: This medication also induces the metabolism of vitamin D, contributing to its deficiency (28,30).
• Cancer Treatments
  • Tamoxifen: Used in breast cancer treatment, tamoxifen has been associated with decreased vitamin D levels (29).
  • Cyclophosphamide and Taxanes (e.g., Paclitaxel): These chemotherapeutic agents can also disrupt vitamin D metabolism, though the exact mechanisms are less well-defined (27).
• Cardiovascular Medications
  • Calcium Channel Blockers (e.g., Verapamil, Diltiazem): These drugs may inhibit the conversion of vitamin D precursors, leading to lower serum levels of vitamin D (27).
  • ACE Inhibitors: Some studies suggest that these medications can be associated with lower vitamin D levels, although the relationship may be influenced by underlying health conditions (27).
• Other Medications
  • Antibiotics: Certain antibiotics, particularly rifampicin, can induce liver enzymes that metabolize vitamin D more rapidly (29,30).
  • Bile Acid Sequestrants (e.g., Cholestyramine): These can interfere with the absorption of fat-soluble vitamins, including vitamin D (28).
  • Orlistat: This weight-loss drug can reduce the absorption of dietary fats, which may also affect the absorption of vitamin D (28).
  • Steroids: Corticosteroids like prednisone can lead to decreased vitamin D metabolism and absorption, contributing to deficiencies (29).

3.5 Lifestyle Factors

Several lifestyle factors influence vitamin D metabolism and can contribute to vitamin D deficiency and resistance:

• High Carbohydrate Diet: High carbohydrate diets may negatively influence vitamin D status and contribute to vitamin D resistance, particularly in specific populations such as pregnant women. Research indicates that a higher carbohydrate intake (≥300 g/day) is significantly correlated with lower levels of 25-hydroxyvitamin D (25(OH)D), which is a key marker for vitamin D status (31). A study involving pregnant women found a significant negative correlation between carbohydrate intake and 25(OH)D levels, highlighting the potential impact of high carbohydrate consumption on vitamin D status (31). Other research indicates that low-carbohydrate diets are associated with higher levels of 25(OH)D, suggesting that reducing carbohydrate intake may be beneficial for improving vitamin D status (32,33).
  • Mechanisms of Interaction
    1. Body Composition and Fat Sequestration: Increased carbohydrate intake can lead to higher body fat composition, which may dilute vitamin D levels in the body. Fat tissue can sequester vitamin D, reducing its bioavailability and potentially impairing its metabolism in the liver (31,32).
    2. Insulin Resistance: High carbohydrate diets can promote insulin resistance, which has been associated with various metabolic disorders. Insulin resistance itself can affect the metabolism of vitamin D, leading to altered levels of its active forms in the body (34).
    3. Dietary Composition: Studies suggest that diets low in carbohydrates, such as ketogenic or low-carbohydrate high-fat (LCHF) diets, may enhance vitamin D status. These diets often include higher amounts of vitamin D-rich foods, which may contribute to better overall vitamin D levels compared to high carbohydrate diets (32,33).
• Toxins: Environmental toxins may also impair the function of enzymes involved in vitamin D activation.
  • Air Pollution and Chemical Exposure: A review article discusses how air pollution, environmental chemicals, and smoking can trigger vitamin D deficiency. The authors suggest potential mechanisms through which these factors may affect vitamin D metabolism, including the disruption of vitamin D synthesis in the skin and alterations in liver metabolism (35).
  • Impact of Nutritional and Environmental Factors: A study highlighted the prevalence of vitamin D deficiency among a population in Saudi Arabia, linking it to various factors, including dietary intake and environmental influences. The findings suggest that even in sunny regions, factors like obesity and limited sun exposure can exacerbate vitamin D insufficiency (36).
  • Endocrine-Disrupting Chemicals (EDCs): Substances like bisphenol A (BPA) and phthalates, commonly found in plastics, can disrupt endocrine functions, including those related to vitamin D. A study analyzed the relationship between urinary levels of phthalate metabolites and bisphenol A with vitamin D levels in U.S. adults. EDCs may alter the expression of enzymes responsible for vitamin D metabolism, leading to reduced efficacy of vitamin D in the body. These findings suggest that higher concentrations of these substances correlate with lower vitamin D levels, indicating that dietary toxins may play a role in vitamin D resistance (35).
• Ultra-Processed Foods (UPF): Recent studies have indicated a concerning relationship between the consumption of ultra-processed foods (UPFs) and vitamin D deficiency.
  • Impact on Vitamin D Levels:
    1. Association with Deficiency: A cross-sectional study conducted in Brazil found that high consumption of UPFs was significantly associated with an increased risk of vitamin D deficiency. Individuals who consumed more UPFs had a 2.05 times higher likelihood of being vitamin D deficient compared to those with lower intake levels. This suggests that UPFs may negatively impact serum vitamin D concentrations, contributing to deficiencies in the population studied (37).
    2. Micronutrient Content: Another study highlighted that diets high in UPFs were inversely related to the intake of several micronutrients, including vitamin D. It was observed that the micronutrient content in diets rich in UPFs was significantly lower than in those based on natural or minimally processed foods. Specifically, the study noted that the higher the proportion of UPFs in the diet, the lower the levels of vitamin D and other essential nutrients (38).
    3. Broader Nutritional Implications: The detrimental effects of UPFs extend beyond vitamin D, as they have been linked to inadequate intake of various micronutrients critical for health. This trend poses significant public health concerns, particularly in populations where UPF consumption is rising rapidly (39,40).
• Excess Seed Oils (Dietary Omega-6 PUFA): High dietary intake of omega-6 polyunsaturated fatty acids (PUFAs) (primarily found in seed oils) has been linked to vitamin D resistance, primarily due to the competitive metabolism of omega-6 and omega-3 fatty acids. Both omega-6 and omega-3 PUFAs are metabolized by the same enzymes, which can lead to an imbalance when omega-6 intake is excessively high compared to omega-3 intake. This imbalance can exacerbate inflammatory processes and potentially interfere with the body's ability to utilize vitamin D effectively. The evidence suggests that high amounts of dietary omega-6 PUFAs can contribute to vitamin D resistance through mechanisms involving inflammation and metabolic dysregulation. A balanced intake of omega-3 and omega-6 fatty acids is crucial for maintaining optimal health and ensuring effective vitamin D metabolism.
  • Omega-6 PUFAs, particularly those derived from linoleic acid, tend to promote inflammation. Chronic inflammation can alter metabolic pathways, potentially leading to vitamin D resistance by affecting the expression of vitamin D receptors or the enzymes involved in vitamin D metabolism (41,42).
  • Nutritional Imbalance: The typical modern diet exhibits a high omega-6 to omega-3 ratio, often ranging from 20:1 to 50:1, which is significantly higher than the recommended ratio of 4:1 to 5:1. This excessive intake of omega-6 fatty acids can lead to an overproduction of pro-inflammatory eicosanoids, which may further contribute to metabolic dysregulation and vitamin D resistance (41,42).
  • Genetic Factors: Variants in genes responsible for fatty acid desaturation (like the FADS gene cluster) can influence how individuals metabolize these fatty acids, potentially leading to varied responses to dietary omega-6 and omega-3 intake. These genetic differences can affect the synthesis of eicosanoids and, consequently, the inflammatory response, which is linked to vitamin D metabolism (42,43).
• Sunshine and Exercise: Adequate sun exposure is crucial for endogenous vitamin D synthesis. However, modern lifestyles often limit sun exposure, contributing to deficiency and resistance. Regular exercise has been shown to improve vitamin D status by enhancing metabolism and reducing inflammation.
  • Lack of exercise can contribute to vitamin D resistance, primarily through its impact on muscle mass and vitamin D metabolism. Research indicates that regular physical activity, particularly resistance training, can enhance vitamin D status by increasing the expression of vitamin D receptors (VDRs) in muscle tissue and promoting the release of vitamin D from muscle cells into circulation (44,45).
  • Mechanisms of Vitamin D Resistance
    1. Muscle Mass and Vitamin D Storage: Resistance exercise is associated with increased muscle mass, which can serve as a reservoir for vitamin D. This muscle tissue can bind and store vitamin D, potentially leading to reduced serum levels of 25(OH)D (the main circulating form of vitamin D) if not adequately supplemented (44).
    2. Exercise-Induced Changes: Acute bouts of exercise have been shown to temporarily increase serum levels of 25(OH)D, indicating that physical activity can enhance vitamin D metabolism. For instance, studies have demonstrated that even a single session of exercise can elevate vitamin D concentrations shortly after the activity (45,46).
    3. Vitamin D Receptors: Regular exercise may upregulate VDR expression in muscles, enhancing the body's ability to utilize vitamin D effectively. This is crucial because vitamin D plays a significant role in muscle function and overall physical performance (46,47).
    4. Seasonal and Environmental Factors: The benefits of exercise on vitamin D status can also be influenced by seasonal variations in sunlight exposure, which is the primary source of vitamin D. Individuals who are more sedentary may miss out on the natural vitamin D synthesis that occurs with outdoor physical activity (44,46).
• Sleep: Poor sleep quality can disrupt the circadian rhythm, which in turn affects hormone levels and vitamin D metabolism. Adequate sleep is essential for maintaining optimal vitamin D levels and reducing resistance.
  • Poor sleep has been linked to vitamin D resistance, with emerging evidence suggesting that vitamin D deficiency (VDD) may exacerbate sleep disorders and poor sleep quality. The interplay between poor sleep and vitamin D resistance highlights the importance of maintaining adequate vitamin D levels for optimal sleep health. While there is promising evidence linking VDD to sleep disorders, further high-quality studies are needed to establish causal relationships and clarify the mechanisms involved
  • Relationship Between Vitamin D and Sleep
    1. Epidemiological Evidence: Studies indicate that individuals with VDD are at a significantly higher risk of experiencing sleep disorders. A meta-analysis involving 9,397 participants found that those with low serum vitamin D levels had increased odds of poor sleep quality, short sleep duration, and excessive daytime sleepiness. Specifically, participants with serum 25(OH)D levels below 20 ng/mL had a 1.5-fold increased risk of sleep disorders (48,49).
    2. Biological Mechanisms: The association between vitamin D and sleep regulation is biologically plausible. Vitamin D receptors are present in the brain, and vitamin D may influence sleep through its role in regulating the serotonergic system, which is crucial for sleep-wake cycles (50,51).
    3. Interventional Studies: Some interventional studies have suggested that vitamin D supplementation can improve sleep quality. For instance, a randomized controlled trial reported that vitamin D supplementation in veterans increased sleep duration. However, results have been inconsistent across different studies, with some showing no significant improvement in sleep from vitamin D supplementation (49,52).
  • Implications of Poor Sleep on Vitamin D Levels
    1. Poor sleep can also affect vitamin D metabolism and its effectiveness in the body. Chronic sleep deprivation may lead to alterations in metabolic processes, including those involved in vitamin D synthesis and utilization, potentially contributing to a cycle of deficiency and resistance (48,51).

3.6 Insufficiency/Deficiency of Other Vitamins and Micronutrients

Vitamin D metabolism is closely linked with other micronutrients, and deficiencies in these can exacerbate vitamin D resistance:

• Nutritional Deficiencies: A study examined the correlation between dietary intake of vitamin D and calcium and the prevalence of vitamin D deficiency. It emphasized that inadequate dietary sources, compounded by environmental toxins, can lead to significant health issues related to vitamin D metabolism (36).
• Vitamin C: Research indicates that vitamin C deficiency can impair the immune-modulating effects of vitamin D. Vitamin C may enhance the effects of vitamin D, particularly in improving metabolic health and immune function.
  1. Metabolic Health: A study found that both vitamin C and vitamin D3 supplementation improved metabolic parameters in obese mice, suggesting a synergistic effect on metabolic health. The combination of these vitamins significantly altered the gut microbiota, enhancing its diversity and overall health, which is crucial for metabolic regulation (53).
  2. Immune Function: Vitamin C is known for its role in immune support, and its supplementation has been associated with improved immune responses. For instance, vitamin C can enhance the function of neutrophils and other immune cells, potentially aiding in the body's response to infections. This immune-boosting property may complement the effects of vitamin D, which also plays a vital role in immune regulation (54-56).
  3. Clinical Implications: The combined supplementation of vitamin C and vitamin D has been suggested to improve outcomes in individuals with metabolic syndrome, highlighting their potential benefits in clinical settings. Vitamin C may help mitigate some of the resistance associated with vitamin D deficiency, thereby improving overall health outcomes (53,57).
• Vitamin B: B vitamins influence vitamin D activity. Research indicates that vitamin B may play a beneficial role in improving vitamin D resistance, particularly in relation to bone health and metabolic functions. The interplay between vitamin B and vitamin D appears to enhance the effectiveness of vitamin D, particularly in contexts like bone health and cognitive function. While vitamin D is crucial for calcium absorption and bone health, the presence of B vitamins may help optimize its metabolic pathways and physiological effects.
  • Interaction Between Vitamins B and D
    • Supplementation Effects: A study showed that supplementation with vitamin D3 and B vitamins significantly decreased bone turnover in elderly individuals. Specifically, the combination of these vitamins improved plasma levels of 25-hydroxyvitamin D and reduced parathyroid hormone levels, which are critical for bone metabolism (58).
    • Positive Correlation: Another study highlighted a positive association between plasma levels of 25-hydroxyvitamin D and both folate and vitamin B12 in adolescents. This suggests that adequate levels of B vitamins may support the metabolism and effectiveness of vitamin D (59,60).
    • Cognitive and Memory Benefits: Research also indicates that vitamin B12 and folate can help reverse cognitive impairments associated with vitamin D deficiency. This underscores the potential of B vitamins to enhance the overall effectiveness of vitamin D in various physiological processes, including cognitive functions (61).
• Vitamin K2 works synergistically with vitamin D to regulate calcium deposition, and its deficiency can impair the effectiveness of vitamin D.
  • Vitamin K2 enhances vitamin D effectiveness: Recent research indicates that vitamin K2 may enhance the effectiveness of vitamin D, particularly in improving vitamin D resistance and overall health outcomes related to bone and cardiovascular health. The interplay between vitamins D and K2 suggests that their combined supplementation may not only improve bone health and insulin sensitivity but also enhance cardiovascular health and immune function. This synergistic relationship underscores the importance of considering both vitamins together in dietary and supplementation strategies, particularly for individuals at risk of deficiencies or related health issues.
  • Synergistic Effects of Vitamins D and K2
    • Bone Health: Vitamin D is crucial for calcium absorption, while vitamin K2 directs calcium to the bones and helps prevent its deposition in arteries. Studies have shown that combined supplementation of vitamins D3 and K2 can lead to significant improvements in bone mineral density (BMD) and a decreased risk of osteoporosis. This synergistic effect is thought to be due to vitamin K2's role in activating proteins that are essential for bone formation and mineralization, such as osteocalcin, which requires vitamin K for its activation (62-64).
    • Insulin Sensitivity: Supplementation with vitamin K2 has been associated with improved insulin sensitivity, particularly in individuals with type 2 diabetes. Research indicates that vitamin K2 can reduce insulin resistance, as evidenced by decreased HOMA-IR values in patients receiving vitamin K2 supplementation. This suggests that vitamin K2 may play a role in enhancing the metabolic effects of vitamin D, thereby improving glucose metabolism and potentially reducing the risk of diabetes-related complications (65).
    • Cardiovascular Health: The combination of vitamins D and K2 may also benefit cardiovascular health by preventing arterial calcification. Vitamin K2 activates matrix GLA protein (MGP), which inhibits the calcification of arteries. This protective effect is particularly important as vitamin D alone may not provide the same level of protection against arterial calcification (63,64).
    • Immune Function: Both vitamins are implicated in supporting immune function. Vitamin D enhances the immune response, while vitamin K2 has been shown to modulate inflammation. Together, they may help improve immune responses and reduce the risk of inflammatory diseases (63,66).
• Magnesium plays a crucial role in the activation of vitamin D. It is a cofactor for the enzymes that convert vitamin D into its active form, calcitriol. Low magnesium levels can impair vitamin D metabolism, leading to reduced effectiveness of vitamin D supplementation and potentially contributing to vitamin D resistance (67,68).
• Zinc is another essential micronutrient that supports the immune system and may influence vitamin D metabolism. It is involved in the activity of vitamin D receptors (VDRs), which are necessary for the biological actions of vitamin D. Adequate zinc levels can enhance the body's response to vitamin D, potentially improving its efficacy in promoting health (68,69).
• Selenium has antioxidant properties and may play a role in enhancing the immune response. Some studies suggest that selenium can influence vitamin D metabolism and receptor activity, although more research is needed to clarify this relationship (69).
• Calcium is closely linked with vitamin D as it is essential for the absorption of calcium in the gut, which is one of vitamin D's primary functions. Adequate calcium levels can support the overall effectiveness of vitamin D, particularly in maintaining bone health and preventing conditions like osteoporosis (67,69).

4. Hormonal Influences on Vitamin D Resistance

4.1 Melatonin:

Melatonin, the hormone responsible for regulating sleep-wake cycles, has been shown to interact with vitamin D metabolism. Adequate melatonin levels may enhance vitamin D receptor expression, thereby reducing resistance. Disrupted melatonin production, often due to poor sleep, can negatively impact vitamin D metabolism.

• Melatonin Insufficiency and Vitamin D Resistance: There is growing evidence that melatonin insufficiency can contribute to vitamin D resistance. Melatonin insufficiency, often caused by factors like overexposure to artificial light at night, may contribute to vitamin D resistance by disrupting the normal functioning of the vitamin D receptor and signaling pathways. Ensuring adequate melatonin production by maintaining proper light/dark cycles may be important for optimizing vitamin D status and function.
• Melatonin and vitamin D have many similarities - they are both hormones that affect multiple systems through immune-modulating and anti-inflammatory functions. Melatonin is often referred to as the "hormone of darkness" since its production is stimulated by darkness and suppressed by light exposure (70).
• Melatonin levels are inversely related to the severity of multiple sclerosis and its relapses. Vitamin D deficiency is also associated with an increased risk of MS. Both melatonin and vitamin D play a critical role in blood-brain barrier integrity (71).
• A study found that correcting vitamin D insufficiency can positively affect melatonin levels and contribute to the treatment of sleep disorders related to melatonin deficiency. There was a moderate positive correlation between melatonin and vitamin D levels (72).
• Vitamin D acts on melatonin synthesis through central receptors found in areas of the brain that regulate sleep. A case report found that combined treatment of vitamin D with melatonin helped improve chronic insomnia symptoms (73).
• Melatonin can bind to the vitamin D receptor, resulting in an enhancement of vitamin D's signaling effects and subsequent cellular activities (74-76). This suggests there may be crosstalk between the two hormones.

4.2 HPA Axis

The hypothalamic-pituitary-adrenal (HPA) axis regulates the body's stress response, and chronic stress can lead to dysregulation of this axis. Cortisol, the primary stress hormone, can inhibit vitamin D metabolism and reduce the expression of VDRs, contributing to resistance.

• Adrenal insufficiency contributing to vit D resistance: Adrenal insufficiency and vitamin D resistance appear to be interconnected, with evidence suggesting that adrenal dysfunction can influence vitamin D metabolism and action in the body. Adrenal insufficiency may contribute to vitamin D resistance through complex interactions involving hormonal regulation and immune response.
  • Relationship Between Adrenal Insufficiency and Vitamin D
    • Vitamin D's Role in Adrenal Function: Vitamin D is essential for various bodily functions, including immune response and hormone regulation. Studies indicate that vitamin D deficiency may exacerbate adrenal insufficiency, particularly in critical illness scenarios, where both conditions can negatively impact cardiovascular and immune systems (77,78).
    • Mechanisms of Resistance: The mechanisms underlying vitamin D resistance in the context of adrenal insufficiency are not fully understood. However, it is hypothesized that low levels of vitamin D might impair adrenal hormone production, particularly cortisol, which is crucial for stress response and metabolic functions. Some research suggests that vitamin D may modulate the adrenal response to stress, potentially influencing cortisol synthesis and secretion (79,80).
    • Clinical Observations: In patients with conditions like Addison's disease, which is characterized by adrenal insufficiency, vitamin D levels tend to be lower. This deficiency may contribute to the disease's symptoms and complications, suggesting a potential therapeutic role for vitamin D supplementation in managing adrenal insufficiency (77,81).
    • Research Findings: A systematic review highlighted that vitamin D deficiency is associated with various adrenal disorders, and the under-expression of vitamin D receptors (VDR) in adrenal tissues may contribute to the resistance observed in these patients. Additionally, vitamin D's immunomodulatory effects could play a protective role in autoimmune adrenal diseases, further complicating the relationship between these two factors (77,78).

4.3 Thyroid

Thyroid hormone status significantly influences vitamin D metabolism and sensitivity, contributing to vitamin D resistance. This relationship is complex and multifaceted, involving both central and peripheral mechanisms.

• Thyroid Hormones and Vitamin D Interaction: Hypothyroidism has been associated with vitamin D deficiency, and this relationship may contribute to vitamin D resistance in affected individuals.
  • Hypothyroidism, characterized by insufficient production of thyroid hormones, can lead to various metabolic imbalances, including alterations in vitamin D metabolism. Studies have shown that individuals with hypothyroidism, particularly autoimmune forms like Hashimoto's thyroiditis, often exhibit lower levels of vitamin D. For instance, a significant percentage of patients with overt or subclinical hypothyroidism were found to have vitamin D deficiency, highlighting a strong correlation between these conditions (82,83).
  • Mechanisms of Vitamin D Resistance: Vitamin D's role in thyroid function is complex. It is known to modulate thyroid hormone secretion and may influence the thyroid's response to stimulating hormones. Vitamin D receptors (VDR) and thyroid-stimulating hormone (TSH) receptors share structural similarities, suggesting that vitamin D may directly affect TSH secretion and thyroid hormone production. However, in hypothyroid patients, the efficacy of vitamin D may be compromised, leading to a state of resistance where the expected physiological responses to vitamin D supplementation are diminished (84,85).
  • Implications for Treatment: Research indicates that vitamin D supplementation can improve serum vitamin D levels and may help lower TSH in hypothyroid patients. However, the extent of its effectiveness can vary, and some individuals may not respond adequately to supplementation due to underlying resistance mechanisms (84,86). This suggests that monitoring vitamin D levels and considering supplementation could be beneficial, especially for those with hypothyroidism, but the response may not be uniform across all patients (87,88).
• Thyroid Hormone Resistance: Recent studies indicate that thyroid hormone resistance can be associated with altered vitamin D metabolism. Both high and low levels of vitamin D have been shown to affect the sensitivity of the thyroid hormone feedback mechanism, indicated by changes in the thyroid feedback quartile index (TFQI) and other related metrics. These findings suggest that vitamin D levels are closely associated with the thyroid's ability to respond effectively to thyroid-stimulating hormone (TSH) (89,90).
  • Mechanisms of Interaction: Vitamin D appears to exert a direct effect on thyroid function by binding to vitamin D receptors (VDR) in thyroid cells. This binding can inhibit TSH receptor activity, thereby reducing the stimulation of thyroid hormone production. Furthermore, vitamin D is involved in the regulation of deiodinase enzymes, which are crucial for converting thyroxine (T4) into the more active triiodothyronine (T3). This conversion is essential for maintaining normal thyroid hormone levels and function (85,89,91).
  • Vitamin D Deficiency and Thyroid Dysfunction**: There is a notable association between vitamin D deficiency and various thyroid disorders, particularly hypothyroidism. Studies have demonstrated that individuals with hypothyroidism often have significantly lower serum levels of 25-hydroxyvitamin D compared to healthy controls. This deficiency may exacerbate thyroid dysfunction, leading to a cycle of worsening vitamin D status and thyroid hormone resistance (85,90,92).
  • Clinical Implications: Understanding the interplay between thyroid hormones and vitamin D is crucial for managing conditions such as autoimmune thyroid diseases and hypothyroidism. Adequate vitamin D levels may enhance thyroid hormone sensitivity and improve overall thyroid function. Conversely, vitamin D supplementation in deficient individuals may lead to improved thyroid hormone levels and sensitivity, although the exact mechanisms require further investigation (84,90,91).

4.4 Sex Hormones

• Estrogen imbalance contributes to vit D resistance: Estrogen imbalance can significantly influence vitamin D resistance, with both hormones interacting in complex ways that affect overall health, particularly in women. Estrogen imbalance can contribute to vitamin D resistance through its regulatory effects on vitamin D metabolism and receptor expression. Addressing vitamin D deficiency and maintaining hormonal balance is crucial for overall health, particularly in women experiencing hormonal disorders. Further research is needed to fully understand these interactions and their implications for treatment strategies.
  • Estrogen's Role in Vitamin D Metabolism: Vitamin D is essential for the synthesis of estrogen, as it regulates enzymes involved in estrogen production, such as aromatase. This enzyme converts androgens into estrogens, thus influencing estrogen levels in the body. Studies have shown that vitamin D deficiency can lead to decreased aromatase activity, resulting in lower estrogen levels, which can contribute to hormonal imbalances (93-95).
  • Vitamin D and Hormonal Regulation: Conversely, vitamin D also plays a crucial role in maintaining hormonal balance. It has been found that vitamin D deficiency is common among women with conditions like polycystic ovary syndrome (PCOS), which is characterized by hyperandrogenism and irregular menstrual cycles. In these cases, vitamin D supplementation has been shown to improve fertility and regulate menstrual cycles by positively influencing estrogen levels (94,95).
  • Consequences of Estrogen Imbalance: An imbalance in estrogen levels can lead to various health issues, including menstrual irregularities, infertility, and increased risk of metabolic syndrome. Women with low vitamin D levels often exhibit higher levels of androgens, which can exacerbate estrogen-related disorders (94,96).
  • Vitamin D Resistance: Vitamin D resistance can occur in the presence of hormonal imbalances, particularly when estrogen levels are disrupted. This resistance may manifest as insufficient biological responses to vitamin D, despite adequate levels of the vitamin in the bloodstream. Research indicates that estrogen influences the expression of vitamin D receptors, which are critical for the hormone's action in the body. Therefore, an imbalance in estrogen can impair vitamin D's effectiveness, leading to resistance (94,97).
• Progesterone imbalance contributing to Vit D resistance: Progesterone imbalance and vitamin D resistance are interconnected issues that can significantly impact women's reproductive health. Progesterone imbalance may contribute to vitamin D resistance, and addressing vitamin D deficiency could be beneficial in restoring hormonal balance and improving reproductive health outcomes. Further research is necessary to clarify the mechanisms involved and to establish effective treatment protocols for women experiencing these issues. Research indicates that vitamin D plays a crucial role in the synthesis and regulation of reproductive hormones, including progesterone.
  • Progesterone and Vitamin D Interaction: Studies have shown that vitamin D deficiency can lead to hormonal imbalances, which may exacerbate conditions like polycystic ovary syndrome (PCOS). Women with PCOS often exhibit low levels of vitamin D, which is associated with increased insulin resistance and hormonal dysregulation, including elevated androgen levels and disrupted progesterone synthesis (94,98).
  • Vitamin D has been found to enhance progesterone synthesis in ovarian cells. However, the direct correlation between serum vitamin D levels and progesterone production remains unclear, as progesterone levels primarily depend on the function of the corpus luteum during the menstrual cycle (97,98).
  • Implications for Reproductive Health: Low vitamin D levels have been linked to various reproductive issues, including infertility and irregular menstrual cycles. Adequate vitamin D levels are associated with improved fertility outcomes, such as higher quality embryos in in vitro fertilization (IVF) patients and increased chances of implantation and pregnancy (98).
• Imbalanced Progesterone/Estrogen Ratio and Vitamin D Resistance: An imbalanced progesterone to estrogen ratio, characterized by progesterone resistance and estrogen dominance, can contribute to vitamin D resistance through epigenetic alterations, gene mutations, and disruption of the complex regulatory mechanisms between vitamin D and estrogen.
  • Progesterone Resistance in the Endometrium: Progesterone resistance, characterized by endometrial unresponsiveness to progesterone, leads to dysregulation of epithelial and stromal gene networks in the endometrium. This imbalance between progesterone and estrogen actions from one menstrual cycle to another induces abnormal changes in the endometrium, potentially contributing to the development of endometrial disorders like endometriosis, adenomyosis, PCOS, and endometrial hyperplasia (99).
  • Epigenetic Alterations: Epigenetic changes, such as hypermethylation, can reduce progesterone receptor (PGR) expression in the endometrium (99). This leads to progesterone unresponsiveness and disrupts the normal functions of the endometrium.
  • Gene Mutations: Somatic mutations in endometrial epithelial cells, particularly in the KRAS gene, are observed in adenomyosis co-occurring with endometriosis (99). These mutations are associated with downregulated PGR expression, potentially contributing to progesterone resistance.
  • Vitamin D and Estrogen Interactions:
    • Vitamin D regulates the activity of enzymes involved in estrogen synthesis, such as aromatase (95). By modulating these enzymes, vitamin D indirectly influences estrogen levels in the body. Vitamin D receptors are present in various reproductive tissues, and when activated by vitamin D, they can affect the transcription of genes that regulate hormone production, including estrogen (95).
    • Estrogen plays a crucial role in regulating the menstrual cycle, reproductive health, bone health, and cardiovascular health. An imbalance in estrogen levels can impact these processes. Vitamin D, in conjunction with estrogen, helps maintain bone health (95).
• Testosterone insufficiency contributing to vitamin D resistance: Testosterone insufficiency and vitamin D resistance are interconnected issues that have garnered significant attention in recent research.
  • Vitamin D Deficiency and Testosterone Levels: Several studies indicate that low levels of vitamin D (specifically 25-hydroxyvitamin D) correlate with lower testosterone levels in men. For instance, a study involving men with chronic spinal cord injuries found that vitamin D deficiency was associated with significantly lower total and free testosterone levels, suggesting a potential independent link between the two hormones (100).
  • Impact of Vitamin D Supplementation: The effects of vitamin D supplementation on testosterone levels remain inconclusive. Some randomized controlled trials have shown no significant increase in testosterone levels following vitamin D supplementation in men with normal baseline testosterone (101). Conversely, other studies suggest that vitamin D supplementation may help improve testosterone levels in men who are deficient, particularly in cases of obesity where both vitamin D and testosterone deficiencies are prevalent (102,103).
  • Common Mechanisms: The relationship between vitamin D and testosterone may be influenced by shared risk factors such as obesity and lifestyle choices. For example, body mass index (BMI) has been shown to mediate the association between vitamin D and testosterone, indicating that obesity may obscure the direct effects of vitamin D on testosterone production (102). Additionally, vitamin D receptors are present in Leydig cells, which are responsible for testosterone production, suggesting a potential role for vitamin D in regulating testosterone synthesis (101).

5. Other Factors that Improve Vitamin D Resistance

5.1 Low Carb Ketogenic Diet Improves Vitamin D Resistance

Recent research indicates that low-carbohydrate diets, particularly ketogenic diets, may improve vitamin D metabolism and resistance.

• Effects of Low-Carbohydrate Diets on Vitamin D
  • Increased Vitamin D Levels: Studies have shown that ketogenic diets, which are low in carbohydrates and high in fats, often lead to increased circulating levels of vitamin D. This effect is attributed to several mechanisms, including changes in fat metabolism, weight loss, and alterations in the hormonal environment that accompanies such diets (32,33).
  • Comparison with Other Diets: A study comparing low-carbohydrate-high-fat (LCHF) diets with traditional diets found that participants on the LCHF diet had significantly higher plasma concentrations of 25-hydroxycholecalciferol (25(OH)D), a key marker for vitamin D status. Specifically, the LCHF group had an average concentration of 34.9 ng/mL compared to 22.6 ng/mL in those following a traditional Eastern European diet (33).
  • In a study of 56 obese adults, those prescribed a very low-calorie ketogenic diet (VLCKD) had a significant increase in serum 25(OH)D concentrations from 18.4 ± 5.9 to 29.3 ± 6.8 ng/mL after 12 months, while the standard hypocaloric Mediterranean diet group showed no significant change (104).
  • For every kilogram of weight loss on the VLCKD, vitamin D levels increased by 0.39 ng/mL, compared to only 0.13 ng/mL per kg lost on the standard diet (104).
  • The KD appears to alter vitamin D metabolism through several mechanisms, including changes in macronutrient intake, status of other fat-soluble vitamins, weight loss, hormonal changes, and effects on gut microbiota (32).
  • Mechanisms of Action: The potential mechanisms through which low-carbohydrate diets enhance vitamin D status include the production of ketone bodies, which may influence the metabolism of fat-soluble vitamins, including vitamin D. Additionally, weight loss associated with these diets could reduce fat mass, which is inversely related to vitamin D levels (32,33).
    • Insulin Sensitivity: Low-carbohydrate diets have also been shown to improve insulin sensitivity, which is beneficial for individuals with insulin resistance. Improved insulin sensitivity can further enhance the metabolism and utilization of vitamin D in the body (34,105).
  • However, some studies have suggested the KD may negatively impact bone health by increasing urinary calcium excretion and potentially reducing bone mineral content, especially in children (106). More research is needed on the long-term effects.

5.2 Intermittent Fasting Improves Vitamin D Resistance

Recent studies indicate that intermittent fasting and prolonged fasting can improve vitamin D levels and its metabolism, particularly in individuals with various health conditions.

• Effects of Prolonged Fasting on Vitamin D: Both intermittent and prolonged fasting have shown promise in enhancing vitamin D levels and may serve as beneficial strategies in managing vitamin D resistance and related health conditions.
  • Study Findings: A randomized controlled trial involving 52 participants demonstrated that a 10-day medically supervised fasting regimen significantly increased vitamin D levels compared to a normal diet. The fasting group (FG) showed a notable rise in vitamin D levels (p = 0.003) alongside improvements in vitality and quality of life metrics (107).
  • Mechanisms of Action: Fasting appears to stimulate vitamin D metabolism. In a separate study, participants who underwent 8 days of fasting exhibited significant increases in specific vitamin D metabolites, suggesting that fasting may enhance the body's ability to utilize vitamin D effectively (108).
  • Correlation with Health Outcomes: The positive effects of fasting on vitamin D levels are particularly relevant in the context of metabolic health. Improved vitamin D status is associated with better outcomes in conditions like type 2 diabetes, where fasting may also enhance insulin sensitivity and reduce inflammation (109).
  • Implications for Vitamin D Resistance: The findings suggest that fasting could be a potential therapeutic approach to address vitamin D resistance, which is often linked to obesity and metabolic disorders. By improving vitamin D levels, fasting may help mitigate some of the health issues associated with vitamin D deficiency, such as immune dysfunction and metabolic disturbances (107,109).

5.3 Near-Infrared (NIR) and Photobiomodulation Therapy (PBMT)

Recent research indicates that Near-Infrared (NIR) and Photobiomodulation Therapy (PBMT) may play a significant role in improving vitamin D resistance and overall health benefits, through mechanisms that enhance vitamin D synthesis and mitigate chronic disease factors.

• Vitamin D Synthesis: NIR light exposure has been linked to improved vitamin D synthesis in the skin. Studies suggest that red and NIR light can enhance the skin's ability to produce vitamin D when exposed to UV light, potentially leading to better vitamin D status in individuals who may otherwise be resistant to its effects (110,111).
• Health Outcomes: PBMT has shown promise in improving various health conditions. It is believed that the benefits associated with sunlight exposure may extend beyond vitamin D production to include other physiological effects mediated by red and NIR light. For instance, PBMT has been associated with reduced oxidative stress and inflammation, which are critical factors in chronic diseases (112,113).
• Clinical Evidence: While the traditional view has focused on vitamin D supplementation, emerging evidence suggests that the effects of NIR and PBMT could explain the health benefits attributed to sunlight exposure. Randomized controlled trials are currently exploring the efficacy of PBMT in treating chronic diseases, indicating a shift in focus from solely vitamin D supplementation to the broader implications of light therapy (113,114).
• Skin Health: PBMT may also contribute to skin health by increasing epidermal thickness, which could enhance the skin's capacity to synthesize vitamin D. This process suggests that individuals using PBMT might experience improved vitamin D absorption during subsequent UV exposure, further supporting the idea of its role in vitamin D resistance (111).

5.4 Methylene Blue and Vitamin D Resistance

Research indicates that methylene blue may play a role in enhancing vitamin D resistance, particularly in the context of viral infections such as those caused by human cytomegalovirus (HCMV).

• Mechanism of Action: Methylene blue has been studied for its effects on various cellular pathways. In the context of HCMV, it has been shown to influence the transcriptional regulation of vitamin D receptor (VDR), which is crucial for mediating the effects of vitamin D in the body. Specifically, HCMV infection can lead to the dysregulation of the transcriptional repressor Snail, which in turn affects VDR function and contributes to vitamin D resistance. This suggests that methylene blue may help counteract some of the mechanisms that lead to vitamin D resistance during viral infections (115,116).
• Oxidative Stress and Inflammation: Vitamin D is known to protect against oxidative stress and inflammation, which are often exacerbated during viral infections. Methylene blue's properties as an antioxidant could potentially complement vitamin D's effects, thereby improving cellular responses to oxidative stress and inflammation (116,117).
• Clinical Implications: The combination of methylene blue with vitamin D could be explored further in clinical settings, particularly for patients suffering from infections that induce vitamin D resistance. This combination may enhance therapeutic outcomes by restoring the functionality of the VDR pathway, which is essential for vitamin D's protective effects against various diseases, including viral infections (115,116).

5.5 Stem Cells

The administration of stem cells in conjunction with vitamin D has shown promising results in improving vitamin D resistance, particularly in the context of metabolic and inflammatory conditions, by addressing oxidative stress, enhancing differentiation, and regulating immune responses.

• Effects of Stem Cells and Vitamin D
  • Stem Cell and Vitamin D Combination Therapy for Diabetes: Mesenchymal stem cells (MSCs) and vitamin D have shown promising effects in improving diabetes when used in combination. The combination of stem cells and vitamin D shows synergistic effects in improving various aspects of diabetes, including osteogenic differentiation, immunomodulation, anti-inflammation, and osseointegration. Animal studies demonstrate the efficacy of this combination therapy in treating diabetes.
    • Synergistic Effect on Osteogenic Differentiation
      • A study found that combining metformin and vitamin D3 accelerated osteogenic differentiation of human adipose tissue-derived MSCs more effectively than either agent alone under high glucose conditions (118).
      • Vitamin D3 stimulated proliferation, expression of pluripotency markers, and osteogenesis of human bone marrow MSCs, partly through SIRT1 signaling (118).
    • Immunomodulatory and Anti-inflammatory Effects
      • Mesenchymal stem cell infusion and vitamin D supplementation may have immunomodulatory actions that could prolong preservation of residual β cells in type 1 diabetes (119).
      • Sufficient levels of vitamin D could preserve residual β cells and have immunomodulatory effects (120).
      • Activating the vitamin D receptor can trigger the anti-inflammatory function of genes to help cells survive under stressed conditions (121).
    • Improved Osseointegration of Implants
      • Vitamin D3 and insulin combined treatment promoted titanium implant osseointegration in diabetic rats (122).
  • Osteogenic Differentiation: Vitamin D is known to enhance the osteogenic differentiation of MSCs. Studies have demonstrated that vitamin D promotes the expression of key integrins involved in cell adhesion and differentiation, which are crucial for the commitment of MSCs to the osteoblastic lineage. This effect is vital for bone regeneration and could play a role in conditions where vitamin D resistance is present (123,124).
  • Immune Regulation: Vitamin D also influences immune cell function, which is relevant in contexts such as graft-versus-host disease (GvHD). It has been observed that vitamin D supplementation may help overcome steroid resistance in GvHD by enhancing the immunosuppressive effects of treatment, potentially through the modulation of inflammatory cytokines (125).

6. Conclusion

Vitamin D resistance is a complex condition that can arise from a combination of genetic, physiological, and lifestyle factors. These factors include poor dietary habits (such as diets high in carbohydrates, seed oils rich in omega-6 fats, and ultra-processed foods), inadequate sleep, lack of exercise and sun exposure, certain prescription medications, exposure to heavy metals and chemical toxins, vitamin and micronutrient deficiencies, hormonal imbalances, and chronic infections. Understanding and addressing these interconnected factors is essential for overcoming vitamin D resistance and ensuring optimal vitamin D status for health.

Vitamin D resistance, whether hereditary or acquired, is influenced by a myriad of factors. This paper emphasizes the importance of a holistic approach that considers the complex interactions between vitamin D and other essential nutrients. The concept of whole-cell nutrition, which highlights the synergy between various vitamins, minerals, and nutrients, is critical in addressing and potentially mitigating vitamin D resistance. Integrative orthomolecular medicine, which focuses on optimizing health through precise nutrient balance, as well as incorporating healthy diets, other lifestyle factors and hormonal balance, presents a promising strategy for managing vitamin D resistance. By adopting a comprehensive, integrative approach, we can enhance the body's ability to utilize vitamin D effectively, leading to improved health outcomes.

The causes of vitamin D resistance discussed in this paper are also key contributors to many other chronic health conditions. Vitamin D resistance is just one mechanism through which these underlying issues can impair health. Achieving optimal health requires a comprehensive approach that includes recognizing, identifying, and managing these root causes, in addition to the intermediary mechanisms and their clinical manifestations.

Integrative orthomolecular medicine should include not only optimal nutrition but also essential interventions such as lifestyle modifications, detoxification, hormonal balance, and advanced treatments like stem cell transplantation and other biological therapies.

With this holistic approach, we have developed an Integrative Orthomolecular Medicine Protocol (126) and have successfully managed a wide range of diseases. Our protocol includes regular testing and vitamin D supplementation, along with a healthy lifestyle that emphasizes a balanced diet low in carbohydrates, omega-6 seed oils, and ultra-processed foods, as well as intermittent fasting, exercise, sun exposure, and quality sleep. We also prioritize optimal nutrition, hormonal balance, detoxification, correction of other root causes, and the application of advanced therapies such as near-infrared photo-biomodulation therapy (PBMT), methylene blue, and stem cell transplantation.

Through this approach, we have observed significant improvements and, in many cases, complete reversal of chronic diseases, including osteoporosis, atherosclerotic cardiovascular disease (ASCVD), type 2 diabetes mellitus (T2DM), cancer, autoimmune diseases, mood disorders, and psychiatric conditions.

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