Description: <b>Short-term fasting (STF)</b> 48 to 72 h before chemotherapy appears to be more effective than intermittent fasting. Preliminary data show that STF is safe but challenging in cancer patients receiving chemotherapy.<br>
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Short-Term Fasting (STF; ~24–72 h water / very low calorie fast) Cancer vs Normal Cell Effects
<table border="1" cellspacing="0" cellpadding="4">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Cells</th>
<th>Normal Cells</th>
<th>Label</th>
<th>Primary Interpretation</th>
<th>Notes</th>
</tr>
<tr>
<td>1</td>
<td>Insulin / IGF-1 signaling</td>
<td>↓ IGF-1 survival signaling (stress)</td>
<td>↓ IGF-1 with adaptive protection</td>
<td>Driver</td>
<td>Differential stress resistance (DSR)</td>
<td>Cancer cells fail to adapt to acute IGF-1 withdrawal; normal cells enter protective mode</td>
</tr>
<tr>
<td>2</td>
<td>AMPK → mTOR nutrient sensing</td>
<td>↑ AMPK; ↓ mTOR (growth crisis)</td>
<td>↑ AMPK; ↓ mTOR (protective quiescence)</td>
<td>Driver</td>
<td>Catabolic enforcement</td>
<td>Rapid mTOR suppression removes anabolic support from tumors</td>
</tr>
<tr>
<td>3</td>
<td>Autophagy (ATG program)</td>
<td>↑ autophagy → metabolic exhaustion</td>
<td>↑ autophagy → cytoprotection</td>
<td>Driver</td>
<td>Catabolic stress vs survival recycling</td>
<td>Autophagy is protective in normal cells but destabilizing in cancer cells</td>
</tr>
<tr>
<td>4</td>
<td>Mitochondrial metabolism / flexibility</td>
<td>↓ metabolic flexibility; ↓ ATP resilience</td>
<td>↑ mitochondrial efficiency</td>
<td>Secondary</td>
<td>Energy crisis vs optimization</td>
<td>Tumors struggle to switch fuels; normal cells adapt</td>
</tr>
<tr>
<td>5</td>
<td>Reactive oxygen species (ROS)</td>
<td>↑ ROS (secondary to energy stress)</td>
<td>↓ ROS</td>
<td>Secondary</td>
<td>Metabolic redox divergence</td>
<td>ROS increase is indirect, arising from metabolic collapse</td>
</tr>
<tr>
<td>6</td>
<td>NRF2 antioxidant response</td>
<td>↔ or insufficient activation</td>
<td>↑ NRF2 (protective)</td>
<td>Adaptive</td>
<td>Stress buffering in normal cells</td>
<td>Normal cells activate antioxidant defenses; tumors often cannot</td>
</tr>
<tr>
<td>7</td>
<td>Cell cycle / proliferation</td>
<td>↓ proliferation / ↑ arrest</td>
<td>↓ proliferation (protective quiescence)</td>
<td>Phenotypic</td>
<td>Growth suppression</td>
<td>Cell-cycle slowdown reflects upstream nutrient deprivation</td>
</tr>
<tr>
<td>8</td>
<td>Therapy sensitivity (chemo / RT)</td>
<td>↑ sensitivity</td>
<td>↓ toxicity</td>
<td>Phenotypic</td>
<td>Differential stress sensitization</td>
<td>STF selectively sensitizes tumors while protecting normal tissue</td>
</tr>
</table>
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Fasting Type vs Effectiveness
<table>
<tr>
<th>Fasting Type</th>
<th>Definition</th>
<th>Primary Metabolic / Signaling Effects</th>
<th>Cancer-Relevant Mechanisms</th>
<th>Evidence Base</th>
<th>Relative Effectiveness*</th>
</tr>
<tr>
<td>Caloric Restriction (CR)</td>
<td>Chronic daily reduction in total caloric intake (typically 20–40%) without malnutrition.</td>
<td>↓ insulin, ↓ IGF-1, ↓ mTOR, ↑ AMPK, ↑ autophagy</td>
<td>Reduces growth signaling; improves metabolic milieu; may slow tumor initiation/growth in models.</td>
<td>Extensive animal data; observational human data.</td>
<td>Moderate–High</td>
</tr>
<tr>
<td>Caloric Restriction Mimetic (CRM)</td>
<td>Non-fasting interventions that mimic CR signaling without major calorie reduction.</td>
<td>↓ mTOR, ↑ AMPK, ↑ autophagy; altered acetyl-CoA/epigenetic tone (context-dependent)</td>
<td>Replicates key CR pathways while preserving nutrition; potential synergy with therapy (context-specific).</td>
<td>Strong mechanistic + preclinical; growing human data.</td>
<td>Moderate–High</td>
</tr>
<tr>
<td>Intermittent Fasting (IF)</td>
<td>Regular cycles of fasting and feeding (e.g., 16:8, 18:6, 20:4).</td>
<td>Periodic ↓ insulin/IGF-1; ↑ fat oxidation; mild ketosis (variable)</td>
<td>Metabolic stress on tumor cells; improved insulin sensitivity; may modulate inflammation.</td>
<td>Good animal data; emerging human data.</td>
<td>Moderate</td>
</tr>
<tr>
<td>Alternate-Day Fasting (ADF)</td>
<td>Alternating 24 h fasting with 24 h ad libitum feeding.</td>
<td>Strong oscillations in insulin/glucose/ketones; improved metabolic switching</td>
<td>Enhanced metabolic flexibility; may promote normal-cell stress resistance.</td>
<td>Animal data strong; limited oncology-specific human data.</td>
<td>Moderate–High</td>
</tr>
<tr>
<td>Short-Term Fasting (STF)</td>
<td>Complete or near-complete fasting for ~24–72 h (often around therapy).</td>
<td>Sharp ↓ IGF-1; ↓ glucose; ↑ ketones; ↑ autophagy</td>
<td>Differential stress resistance (normal-cell protection) and potential tumor sensitization (context-specific).</td>
<td>Strong preclinical; small human trials.</td>
<td>High</td>
</tr>
<tr>
<td>Fasting-Mimicking Diet (FMD)</td>
<td>Low-calorie, low-protein, low-sugar diet for 3–5 days designed to simulate fasting.</td>
<td>↓ IGF-1; ↓ mTOR; ↑ autophagy; partial ketosis</td>
<td>Similar benefits to STF with improved tolerability; may enhance therapy response in some contexts.</td>
<td>Strong animal; increasing human interventional data.</td>
<td>High</td>
</tr>
<tr>
<td>Protein Restriction (PR)</td>
<td>Reduction in total protein or specific amino acids (e.g., methionine restriction).</td>
<td>↓ IGF-1; ↓ mTORC1; altered amino-acid sensing</td>
<td>Targets amino-acid dependencies and growth signaling; may synergize with selected therapies.</td>
<td>Strong mechanistic; animal + early human data.</td>
<td>Moderate–High</td>
</tr>
<tr>
<td>Ketogenic / Very-Low-Carb Diet</td>
<td>Diet inducing sustained ketosis without fasting (variable protein content).</td>
<td>↓ glucose; ↓ insulin; ↑ ketones</td>
<td>May constrain glycolysis-dependent tumors; effects are heterogeneous by cancer type and context.</td>
<td>Mixed animal data; heterogeneous human data.</td>
<td>Low–Moderate</td>
</tr>
<tr>
<td>Time-Restricted Feeding (TRF)</td>
<td>Fixed daily eating window (typically 6–12 h), emphasizing circadian alignment.</td>
<td>Circadian stabilization; modest ↓ insulin exposure; partial metabolic switching</td>
<td>Improves metabolic control; limited deep autophagy unless fasting is long (≥18–20 h).</td>
<td>Early-stage; indirect oncology evidence.</td>
<td>Low–Moderate</td>
</tr>
<tr>
<td>Water-Only Prolonged Fasting</td>
<td>Extended complete fasting (>72 h).</td>
<td>Deep ketosis; strong autophagy; high physiological stress</td>
<td>Potentially strong tumor stress but higher risk and limited controlled oncology study.</td>
<td>Limited / heterogeneous; safety considerations significant.</td>
<td>Uncertain / Not Rated</td>
</tr>
</table>
<pre>
Notes on Effectiveness Ratings
-High: Consistent preclinical efficacy + mechanistic clarity + early human interventional support
-Moderate–High: Strong biology with partial human validation
-Moderate: Solid rationale but limited oncology-specific human data
-Low–Moderate: Indirect or context-dependent effects
-Uncertain: Insufficient or high-risk evidence base
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<table>
<tr>
<th>TRF Pattern</th>
<th>Feeding Window</th>
<th>Fasting Duration</th>
<th>Metabolic Depth</th>
<th>Cancer-Relevant Effects</th>
</tr>
<tr>
<td>14:10 TRF</td>
<td>10 h eating / 14 h fast</td>
<td>14 h</td>
<td>Mild</td>
<td>Improves insulin sensitivity; typically minimal autophagy.</td>
</tr>
<tr>
<td>16:8 TRF</td>
<td>8 h eating / 16 h fast</td>
<td>16 h</td>
<td>Mild–Moderate</td>
<td>Reduces daily insulin/IGF-1 exposure; partial metabolic switching.</td>
</tr>
<tr>
<td>18:6 TRF</td>
<td>6 h eating / 18 h fast</td>
<td>18 h</td>
<td>Moderate</td>
<td>Greater fat oxidation; autophagy initiation more likely (variable).</td>
</tr>
<tr>
<td>20:4 TRF</td>
<td>4 h eating / 20 h fast</td>
<td>20 h</td>
<td>Moderate–High</td>
<td>Lower insulin for longer; early ketosis in some individuals; more “fasting-like.”</td>
</tr>
<tr>
<td>22:2 TRF</td>
<td>2 h eating / 22 h fast</td>
<td>22 h</td>
<td>High (borderline IF)</td>
<td>Strong circadian + metabolic stress; limited tolerability for many.</td>
</tr>
</table>
<pre>
Circadian Timing (Critical for Cancer Relevance)
Early TRF (eTRF)
-Feeding window: ~07:00–15:00 or 08:00–16:00
-Superior reductions in insulin, glucose AUC, and IGF-1 signaling
-Aligns with PER/CRY, BMAL1, CLOCK oscillations
-More favorable for cancer-relevant metabolic control
Late TRF
-Feeding window: ~12:00–20:00 or later
-Weaker insulin and IGF-1 suppression
-Circadian misalignment may blunt benefits
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