When Fasting Backfires: The Hidden Role of Vitamin D in Autophagy

Fasting is often praised for reducing inflammation, improving metabolism, and supporting repair. But what if the very tool meant to heal leads to fatigue, insomnia, or flare-ups? For some patients, fasting doesn’t just underperform. It backfires. And one often overlooked factor may be to blame: vitamin D.

Table of Contents:

1. It Started With a Patient

2. A Study That Changed My Perspective

3. More Than Just Bone Health

4. The Half-Life Problem: A Window Into Fragility

5. New Insight: VDR Polymorphisms and Individualised Response

6. Circadian Considerations: When You Fast Also Matters

7. Who Is Most at Risk

8. What I Now Do Differently

9. The Bigger Picture: Precision Fasting Is the Future

10. Let’s Keep Exploring Together

It Started With a Patient

Not long ago, I sat across from a patient. Let’s call her Anna, who had committed wholeheartedly to a fasting-mimicking protocol.

She was highly motivated. Together, we mapped out every detail: calorie cycling, hydration support, adequate mineral intake, gentle movement, and prioritised rest. Yet by day three, she messaged me. Her energy levels had dropped, her joint pain had returned, and she was waking up at 3 a.m., feeling restless and inflamed.

This was not an unfamiliar scenario. Over the past few years, I have observed a consistent pattern. Some patients, particularly those with chronic inflammatory or autoimmune conditions, do not respond well to fasting protocols. For a long time, I questioned what I might have been overlooking.

I have always regarded fasting as one of the most elegant tools for biological reset. It can promote autophagy, enhance metabolic flexibility, reduce inflammation, and improve mitochondrial efficiency. However, clinical experience eventually pointed me to a pattern that research has only recently begun to clarify. Fasting can backfire when the body lacks one essential cofactor: vitamin D (Zmijewski M. 2019; Min S. et al., 2021; Shabkhizan R. et al., 2023).

A Study That Changed My Perspective

While reviewing literature for my research on circadian biology and metabolic interventions, I came across a 2019 study that reshaped how I approach fasting protocols in clinical practice. The study revealed that fasting suppresses CYP2R1, the hepatic enzyme responsible for converting vitamin D into its circulating form, 25-hydroxyvitamin D (25(OH)D) (Aatsinki S-M. et al., 2019). At the same time, fasting upregulates CYP24A1, the enzyme that breaks down both 25(OH)D and the active form, 1,25-dihydroxyvitamin D (1,25(OH)₂D₃), into inactive metabolites (Aatsinki S-M. et al., 2019).

This dual enzymatic shift significantly alters vitamin D metabolism during fasting. Even a relatively short fasting window may reduce production of active vitamin D while simultaneously accelerating its degradation (Aatsinki S-M. et al., 2019). That insight helped me reinterpret clinical cases like Anna’s. These patients were not failing the protocol. Rather, their vitamin D biology was simply misaligned with the demands of the intervention.

More Than Just Bone Health

In clinical nutrition and systems biology, we have long moved beyond viewing vitamin D as a nutrient limited to skeletal health. I often explain to patients that vitamin D functions as an epigenetic regulator, capable of influencing the expression of more than 1,000 genes, particularly those involved in immune modulation, oxidative stress response, and cellular maintenance processes such as autophagy (Zmijewski M. 2019; Min S. et al., 2021).

The active form of vitamin D, known as calcitriol or 1,25-dihydroxyvitamin D (1,25(OH)₂D₃), binds to the vitamin D receptor (VDR), a nuclear receptor expressed in immune cells, epithelial tissues, neurons, and even within gut microbial signalling pathways (Shabkhizan R. et al., 2023). Upon binding, it promotes the transcription of genes that regulate autophagy, including LC3B and Beclin-1, as well as mitophagy-related genes such as PINK1 and Parkin (Shabkhizan R. et al., 2023).

From a clinical perspective, maintaining adequate vitamin D levels is not merely beneficial during periods of caloric restriction or metabolic reset; it is biologically essential for autophagy to proceed in a coordinated and therapeutic manner (Zmijewski M. 2019).

The Half-Life Problem: A Window Into Fragility

It is often assumed that vitamin D status remains stable during caloric restriction. However, it is essential to distinguish between its two primary forms. The circulating storage form, 25-hydroxyvitamin D (25(OH)D), has a half-life of approximately two to three weeks, whereas the biologically active form, 1,25-dihydroxyvitamin D (1,25(OH)₂D₃), has a much shorter half-life of only four to six hours (Zmijewski M. 2019).

This difference becomes clinically significant during periods of reduced nutrient intake or diminished hepatic enzymatic activity, when tissues may rapidly become deprived of the active hormone at a time when cellular demand for repair is elevated (Zmijewski M. 2019).

This is particularly critical in immune and neural tissues, where autophagic flux is closely regulated by local vitamin D signalling (Min S. et al., 2021).I have observed this in practice. In some cases, caloric restriction was intended to promote regeneration but instead triggered symptoms such as insomnia, neuroinflammation, or immune flare-ups. The issue is often not the intervention itself, but a mismatch between the metabolic demands of the protocol and the individual’s internal biochemical terrain.

New Insight: VDR Polymorphisms and Individualised Response

Emerging research has shown that polymorphisms in the vitamin D receptor (VDR) gene, such as FokI and TaqI, can significantly influence individual responses to vitamin D supplementation. This may help explain why some individuals do not show the expected physiological response, even when serum 25(OH)D levels appear optimal (Usategui-Martín R. et al., 2022).

This phenomenon is evident in clinical settings. I have seen patients with identical serum 25(OH)D values respond in vastly different ways to metabolic protocols. One patient may experience calm and repair, while another reports irritability, fatigue, or autoimmune flare-ups. When I suspect this underlying variability, I often recommend genetic testing for VDR polymorphisms or evaluate indirect markers such as IL-10, TNF-α, or autophagy-related microRNAs.

autophagy

This insight reinforces what I frequently remind colleagues. Functional lab results are valuable, but they provide only part of the picture. The broader genomic context plays a pivotal role in shaping clinical outcomes.

Circadian Considerations: When You Fast Also Matters

Another aspect I find both compelling and clinically significant is the circadian regulation of vitamin D-metabolising enzymes. Both CYP2R1 and CYP24A1 demonstrate diurnal expression patterns, influenced by circadian transcription factors such as BMAL1 and PER2 (Aatsinki S-M. et al., 2019; Dos Santos A. & Galiè M., 2024).

This suggests that the timing of food restriction may meaningfully impact how these enzymes behave. For example, engaging in caloric restriction during the biological night, such as skipping breakfast and lunch while consuming meals later in the evening, may further suppress CYP2R1 activity while increasing breakdown through CYP24A1 (Aatsinki S-M. et al., 2019).

These dynamics carry important implications for intermittent fasting strategies, particularly in individuals with disrupted circadian rhythms, such as night shift workers or those experiencing chronic social jet lag. In clinical practice, I now frequently advise patients to align their fasting windows with daylight hours to synchronise with peripheral clock gene expression and support more consistent metabolic enzyme function.

Who Is Most at Risk?

I see the greatest vulnerability in patients with:

• Chronic inflammation or autoimmunity (RA, MS, Hashimoto’s) (Shabkhizan R. et al., 2023)

• Low baseline 25(OH)D (Zmijewski M. 2019)

• High vitamin D binding protein (DBP) (Aatsinki S-M. et al., 2019)

• Older age or low sun exposure (Zmijewski M. 2019)

• Compromised liver or renal activation pathways (Shabkhizan R. et al., 2023)

• VDR polymorphisms (Panichi L. et al., 2020)

• Mitochondrial dysfunction or low autophagic tone (Min S. et al., 2021)

These patients require more personalised fasting strategies, often preceded by metabolic priming: repleting vitamin D, correcting circadian misalignment, supporting mitochondrial resilience, and managing cortisol before initiating fasting.

What I Now Do Differently

Over time, my protocols for caloric restriction have become more sophisticated and, in many ways, more compassionate. These are three strategies I now integrate into clinical practice:

1. Pre-Loading Vitamin D

Two days prior to the fasting window, I instruct patients to take a one-time bolus of vitamin D, equivalent to five days of their usual maintenance dose. For example, a patient taking 10,000 IU daily would take 50,000 IU as a single pre-load. This approach helps buffer the enzymatic suppression of CYP2R1 and maintains adequate circulating 25(OH)D throughout the fasting period (Aatsinki S-M. et al., 2019; Zmijewski M. 2019).

2. Enzyme-Aware Nutrition

I incorporate targeted compounds such as curcumin, sulforaphane, and omega-3 fatty acids, which may help modulate CYP24A1 activity, downregulate NF-κB-mediated inflammatory signalling, and extend the biological half-life of vitamin D during caloric restriction. While this strategy remains in its early stages, it holds promise for preserving active vitamin D availability (Aatsinki S-M. et al., 2019; Shabkhizan R. et al., 2023).

3. Lipidomics and Transport Considerations

Given that vitamin D is a fat-soluble compound, lipid transport plays a crucial role in its bioavailability. In patients with imbalanced lipid profiles, such as low HDL or elevated oxidised LDL, vitamin D transport and tissue uptake may be impaired. I now include advanced lipid testing as part of the preparatory phase to assess risk and support optimal absorption (Min S. et al., 2021).

The Bigger Picture: Precision Fasting Is the Future

Fasting is not inherently harmful, but it is a powerful physiological intervention. Like any therapeutic tool, it requires discernment, appropriate timing, and individualised clinical context.

If you or your patients have experienced adverse effects during caloric restriction, it is important not to attribute the outcome solely to non-compliance or lack of commitment. In many cases, the issue may stem from a genuine biochemical misalignment, and vitamin D could be a key, yet overlooked, factor.

What is needed now is not more one-size-fits-all protocols, but a model of precision fasting that is grounded in systems biology, circadian regulation, functional nutrition, and genomic individuality.

Let’s Keep Exploring Together

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References:

1. Aatsinki S-M., Elkhwanky M-S., Kummu O., Karpale M., Buler M., Viitala P., Rinne V., Mutikainen M., Tavi P., Franko A., Wiesner R., Chambers K., Finck B., Hakkola J. (2019). Fasting-Induced Transcription Factors Repress Vitamin D Bioactivation, a Mechanism for Vitamin D Deficiency in Diabetes. American Diabetes Association. doi: 10.2337/db18-1050

2. Min S., Masanovic B., Bu T., Matic R., Vasiljevic I., Vukotic M., Li J., Vukovic J., Fu T., Jabucanin B., Bujkovic R., Popovic S. (2021). The Association Between Regular Physical Exercise, Sleep Patterns, Fasting, and Autophagy for Healthy Longevity and Well-Being: A Narrative Review. Frontiers in Psychology. https://doi.org/10.3389/fpsyg.2021.803421

3. Zmijewski M. (2019). Vitamin D and Human Health. MDPI. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms20010145

4. Shabkhizan R., Haiaty S., Sadat Moslehian M., Bazmani A., Sadeghsoltani F., Saghaei Bagheri H., Rahbarghazi R., Sakhinia E. (2023). The Beneficial and Adverse Effects of Autophagic Response to Caloric Restriction and Fasting. Science Direct. doi: 10.1016/j.advnut.2023.07.006

5. Usategui-Martín R., De Luis-Román D-A., Fernández-Gómez J.M., Ruiz-Mambrilla M., Pérez-Castrillón J-L. (2022). Vitamin D Receptor (VDR) Gene Polymorphisms Modify the Response to Vitamin D Supplementation: A Systematic Review and Meta-Analysis. MDPI. Nutrients. https://doi.org/10.3390/nu14020360