The Fine Art & Science of Fasting To Tap Into The Cellular Guardian Angels | Deep Dive

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For this installment of our Health Hot Takes series, I brought in Andrea from my clinical team to grill me on a topic I've spent almost 17 years working with patients on: fasting.

We started with a simple but important point - fasting isn't a trend. Every culture in human history has used it, intentionally or out of necessity, for physical and spiritual reasons - Yom Kippur, Lent, Ramadan - and it's old enough that Hippocrates and Paracelsus both built their practice of medicine around it. Paracelsus actually called fasting "the physician within," which I think is a beautiful way to put it.

One of my favorite tangents in this episode is the real, wild history behind the phrase "the dose makes the poison, the dose makes the medicine." It traces back to a king named Mithridates VI, who spent years dosing himself with tiny amounts of poison to build resistance to assassination. It's basically the ancient blueprint for what we now call hormesis, and fasting is one of the clearest examples of it: a small, intentional stressor that makes your cells more resilient.

We got into the actual mechanics - autophagy, the cell's own cleanup process, sirtuins acting as the cell's guardian angels, and how ketones function as a genuine fourth macronutrient with real anti-inflammatory effects on pathways like NF-kappa B and COX-2. We also covered the practical side people actually ask me about: what you can have during a fast (water, tea, coffee, electrolytes), where bone broth and fiber fit in as a bridge rather than a true fast, and which fasting windows make sense depending on where you're starting from.

The part I'd ask you to sit with most is the closing point: fasting isn't one-size-fits-all, and it isn't meant to be your identity. It's a tool - one you can pick up, put down, and recalibrate as your life changes.

A few of my favorite things we cover in this episode: 

• Why fasting isn't a trend: it's coded into human history and used by every culture - Yom Kippur, Ramadan, Lent - and practiced by the fathers of modern medicine, Hippocrates and Paracelsus
• Paracelsus called fasting "the physician within"
• The wild true story of Mithridates VI, the ancient king who dosed himself with poison, and the real origin of "the dose makes the poison, the dose makes the medicine"
• Hormesis explained: cold plunges, saunas, HIIT/REHIT training, and fasting are all "adversity mimetics" that use small doses of stress to build cellular resilience
• How fasting and the ketogenic diet work through the same mTOR and autophagy pathway - and why mTOR needs to come down sometimes, not stay high all the time
• What autophagy actually is: the cell's own cellular cleanup process, from autophagosome to autolysosome
• Sirtuins as the cell's "guardian angels," and how fasting supports them alongside autophagy
• Ketones as "the fourth macronutrient": how beta-hydroxybutyrate lowers NF-kappa B and COX-2 and crosses the blood-brain barrier
• Why fasting and ketogenic diets are being studied for epilepsy, OCD, schizophrenia, anxiety, and depression
• Food compounds that upregulate autophagy outside of fasting: spermidine (aged cheese, mushrooms, wheat germ) and urolithin A
• What's actually allowed during a fast - water, tea, coffee, electrolytes - and where bone broth and fiber fit as a bridge, not a true fast
• Fasting windows to consider: 12/12, 16/8, 18/6, multi-day fasts, and fasting-mimicking diets (Valter Longo's research out of USC)
• Protein cycling and sparing: why mTOR is sensitive to protein, and when to pull back vs. build
• Who should start conservatively or check in first: people under high stress, low thyroid function, and women tracking their menstrual cycle
• The gut's own circadian rhythm, and how fasting helps reset bacterial overgrowth and dysbiosis

Products Mentioned:

• Heal Your Cells (Dr. Cole's new book with Dr. Josh Axe) - https://drwillcole.com/books-home-page/
• Intuitive Fasting (Dr. Cole's earlier book, foreword by Gwyneth Paltrow) - https://drwillcole.com/books-home-page/
• Liv 120 / Longevity Rx (polyphenol, postbiotic, and electrolyte products) - https://shop.drwillcole.com/collections/longevity-rx
• Ketone-IQ (exogenous ketone) - ketone.com

Protocols/Practices Mentioned:

• Hormesis and "adversity mimetics": cold plunging, sauna (traditional and infrared), HIIT/REHIT training
• The mTOR / autophagy pathway and the fasting-mimicking diet (ketogenic diet, Valter Longo's research)
• Autophagy and mitophagy (cellular and mitochondrial cleanup)
• Sirtuins and AMPK
• Spermidine (aged cheese, mushrooms, wheat germ, spirulina) and urolithin A for autophagy support
• Ketosis / beta-hydroxybutyrate and its effects on NF-kappa B and COX-2
• Fasting windows: 12/12, 16/8, 18/6, and multi-day water fasts
• Protein cycling / protein sparing
• Electrolytes, bone broth, and fiber as fasting bridges or additions
• Menstrual cycle-aware fasting for women

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Happy listening, and we hope you learned a little bit more on the art of being well!

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In Health,

Dr. Will Cole