Sharing an interesting article on intermittent fasting
https://www.zhihu.com/question/2005954269753390531/answer/2010395148404691510
I am writing this while in the middle of a fast, consuming nothing but sugar-free electrolytes. However, my heart is heavy. In the last few days, a top-tier study regarding intermittent fasting (IF) has been published, and it acts as a virtual “death warrant” for the field.
This paper, published in the premier immunology journal Immunity (a Cell sub-journal), coldly reveals the most fundamental and cruel law of life sciences: Evolutionary Trade-offs.
Research Citation: Cell/Immunity - BHB and Long-Lived Plasma Cells
The core message? While we strive to squeeze “metabolic dividends” (longevity, autophagy) out of starvation, nature is quietly draining our “immune moat” as payment.
The Mechanism: BHB as the “Bone Marrow Assassin”
For the past decade, the longevity and keto communities have deified B-hydroxybutyrate (BHB)—the ketone body produced during fasting—as a “miracle molecule.” It was believed to cross the blood-brain barrier to fuel the brain, suppress inflammation, and act as an epigenetic switch for longevity genes.
The Study’s Discovery: This paper exposes BHB’s role as a “hidden assassin” within our bone marrow.
- The Target: Deep within our bone marrow reside Long-Lived Plasma Cells (LLPCs). These are our “permanent munitions factories,” holding the memory of every vaccine (COVID, flu, measles) or infection we’ve ever had. They churn out antibodies for decades; they are the reason you don’t get measles twice.
- The Trigger: A research team from Sun Yat-sen University found that LLPCs possess a receptor called HCAR2. Coincidentally, HCAR2 is the specific binding target for BHB.
- The Fatal Blow: When we fast or maintain ketosis, high concentrations of BHB flood the bone marrow and bind to HCAR2. This triggers a specific signaling pathway: Gαi-cAMP
This pathway forces a massive downregulation of CXCR4 on the surface of the LLPC.
Why does CXCR4 matter? It is the “physical anchor” that keeps LLPCs latched onto the bone marrow stroma. Without this anchor, these antibody factories drift out into the peripheral blood (where they increase nearly 2-fold within 24 hours of fasting) and subsequently undergo Apoptosis (programmed cell death).
The Result: Routine 16:8 fasting, alternate-day fasting, or keto diets may be systematically dismantling your “permanent defense towers” against deadly infections.
Winners and Losers: Sinclair vs. Attia
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The Victim: David Sinclair. As a “fasting fundamentalist,” Sinclair is a “starvation-for-longevity” fundamentalist who has long advocated for eating only one meal a day (OMAD) to maintain extremely high autophagy. This means he spends nearly 20 hours every day being flushed by high concentrations of BHB. This paper directly declares that while he is using fasting to exchange for cellular rejuvenation, he is, at a physical level, “burning down” his own humoral immune memory. Once he encounters a new, highly pathogenic variant virus, his first line of defense will be even more fragile than that of an average person who eats rice and flour.
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The Survivor: Peter Attia. Attia was once a keto and long-fasting fanatic (often doing 3–7 day water fasts). However, in his book Outlive, he announced he was pivoting away from extreme fasting because it consumes vital muscle mass. By switching to a strategy of High Protein + Zone 2 Cardio + Heavy Resistance Training + Minimal Fasting, he accidentally avoided the BHB-mediated destruction of his immune system. (though his involvement in the Epstein affair leading to a professional cliff-dive and the loss of several jobs is another matter…).
The “7-Day Immune Vacuum”
Is the damage irreversible? Not entirely. The study notes that Memory B Cells (MBCs) are largely unaffected because they lack the HCAR2 receptor.
However, there is a catch. Since the “standing army” (LLPCs) is dead, you lose your “instant shield.” If you encounter a virus:
- Young people: You will get sick for 3–7 days while your Memory B Cells wake up, proliferate, and differentiate into new plasma cells to fight back. It’s an inconvenience.
- The Elderly (70+): That 3–7 day “immune vacuum” is a death trap. It is the window where a simple flu turns into fatal pneumonia.
The Biohacker’s New Playbook: Rational Fasting
The era of “blind, year-round starvation” is over. Here is the strategic pivot for biological hackers:
1. Vaccine Protocol:
If we are preparing to receive any vaccine (Flu, HPV, Shingles, etc.), for 1 week before to 3–4 weeks after, absolutely prohibit any form of fasting (including basic 16:8) and ketogenic diets. During this time, you must eat high-quality carbohydrates (rice, sweet potatoes, etc.) on time, using the insulin triggered by carbs to death-grip the liver’s production of BHB. You must ensure the LLPCs induced by the new vaccine can successfully grow CXCR4 anchors and settle in the bone marrow. The same applies to the recovery period of natural infections (like a severe cold).
2. Avoid the 365-Day Grind:
Do not execute strict 16:8 or keto every single day of the year. Soaking your bone marrow in BHB year-round is chronic suicide. Adopt a gentle 12:12 (circadian rhythm night fasting); this is enough to rest the gut and clear liver glycogen, but not enough to make BHB skyrocket to the threshold that destroys LLPCs.
3. The 14:10 Rule (TRE)
Instead of 16:8, move to 14:10 (e.g., fasting from 8 PM to 10 AM). According to Dr. Satchin Panda, this is “Time-Restricted Eating” (TRE), not true fasting. It allows gut rest and glycogen depletion without hitting the BHB threshold that kills immune cells.
4. Autophagy Mimetics (The “Perfect Solution”)
Since the rule set by nature is “starvation produces ketones (BHB) which kill immune cells,” the perfect workaround is to skip the macro-physical process of liver ketosis and use targeted molecules to “precisely pull the trigger” of energy deprivation inside the cell (such as AMPK/Sirtuins).
- Spermidine: Combined with 14:10. It is currently recognized as the strongest natural autophagy inducer. It enters the cell directly, inhibits acetyltransferases, and forcibly presses the “global autophagy” start button inside the cell.
- Urolithin A: It can precisely target and activate the PINK1/Parkin pathway, forcibly starting mitophagy to dismantle and “clear mines” (old, leaking mitochondria) in the cell.
- Grape Seed Extract (Proanthocyanidins/PCC1): This is not just fasting-mimicking; it is a phenomenal Senolytic (senescent cell clearer). Low doses of PCC1 can precisely induce apoptosis in “zombie cells” without starvation, extending the lifespan of old mice by a staggering 64.2%.
- Metformin: Perfectly mimics fasting, but because it negates exercise gains (and cardio/muscle are more important), it is recommended for use on non-exercise days only. Do not use it long-term. (Berberine or Acarbose are good lower-tier alternatives).
- Rapamycin: The only molecule that absolutely extends lifespan in almost all animal models. It doesn’t go through the “front-end” AMPK, but directly and precisely locks the “back-end” mTORC1 pathway. It can force cells into the deepest autophagy even when you are full and have zero BHB toxicity. Note: Top biohackers use a “pulse therapy” of only once a week under strict medical monitoring.
5. The “Oscillation” Strategy
Create a weekly rhythm of Decomposition and Synthesis:
- Decomposition Days (3 days/week): Non-exercise days. Execute 14:10 fasting, take Spermidine/Urolithin A. Let the cells clean house.
- Synthesis Days (4 days/week): Heavy training days. Stop all autophagy supplements. Eat high protein (Leucine) to spike the mTOR pathway. Force muscle growth and immune cell proliferation.
6. The Quarterly “Nuclear” Clean-up
Once a quarter, perform a 3–5 day fast or FMD (Fasting Mimicking Diet). Yes, you will sacrifice some antibodies. But the trade is worth it. This deep energy deficit kills off “zombie” and pre-cancerous cells. Crucially, when you re-feed, it triggers a burst of Hematopoietic Stem Cells (HSCs), which will repopulate your clean bone marrow with fresh, young, and more vigorous Long-Lived Plasma Cells.
Conclusion
Don’t just stop eating. Understand the mechanism. We want a deep cleaning of our cellular “house,” but we shouldn’t burn the “security system” down to achieve it.
