The Longevity Index

Fasting

The TL;DR

Fasting is one of the most potent interventions for activating cellular repair mechanisms and improving metabolic health. Periodic nutrient deprivation triggers autophagy, enhances insulin sensitivity, shifts metabolism toward fat oxidation, and inhibits growth-promoting pathways like mTOR while activating longevity pathways like AMPK. Evidence supports time-restricted eating (12-16 hour daily fasts) for metabolic health and periodic longer fasts or fasting-mimicking diets for deeper cellular rejuvenation. Individual responses vary; fasting is not appropriate for everyone.

Accessibility Level

Level 2 (Optimization): Fasting builds upon the dietary foundations and should be implemented after establishing consistent whole-food eating patterns. Start with simple time-restricted eating before progressing to longer fasting protocols. Fasting is free but requires metabolic flexibility and careful attention to contraindications.

The Science of Fasting and Longevity

Why Fasting Activates Longevity Pathways

Fasting represents an evolutionarily conserved stressor that triggers adaptive cellular responses. Throughout human evolution, periods of food scarcity were common, and our physiology developed sophisticated mechanisms to not only survive but thrive during nutrient deprivation. These mechanisms, when activated intentionally, appear to confer significant health and longevity benefits (Longo & Mattson, 2014).

The fundamental insight is that constant nutrient availability, while preventing starvation, also prevents activation of cellular maintenance programs. As Valter Longo describes it, the body operates in two modes: “growth mode” when nutrients are abundant, and “repair mode” when nutrients are scarce. Modern eating patterns keep us perpetually in growth mode, potentially accelerating aging (Longo & Panda, 2016).

The Nutrient-Sensing Pathways

Four interconnected nutrient-sensing pathways govern the cellular response to fasting:

1. mTOR (Mechanistic Target of Rapamycin)

mTOR is a master regulator of cell growth and metabolism. When amino acids and insulin are abundant, mTOR is activated, promoting protein synthesis, cell proliferation, and inhibiting autophagy. Chronic mTOR activation is associated with accelerated aging and age-related diseases (Saxton & Sabatini, 2017).

Fasting inhibits mTOR through:

  • Reduced amino acid availability (especially leucine)
  • Lower insulin and IGF-1 signaling
  • AMPK activation (which directly inhibits mTOR)

2. AMPK (AMP-Activated Protein Kinase)

AMPK is the cellular energy sensor, activated when the AMP:ATP ratio rises (indicating low energy status). AMPK activation during fasting (Herzig & Shaw, 2018):

  • Stimulates glucose uptake and fatty acid oxidation
  • Promotes mitochondrial biogenesis
  • Activates autophagy
  • Inhibits mTOR and anabolic processes
  • Enhances insulin sensitivity

3. Sirtuins

Sirtuins (particularly SIRT1 and SIRT3) are NAD+-dependent deacetylases activated during fasting. They regulate metabolism, stress resistance, and longevity through (Guarente, 2013):

  • Deacetylation of metabolic enzymes
  • Activation of PGC-1alpha (mitochondrial biogenesis)
  • Enhanced DNA repair
  • Reduced inflammation

4. Insulin/IGF-1 Signaling

Reduced insulin and IGF-1 during fasting shifts cells from growth to maintenance mode. Lower insulin/IGF-1 signaling is consistently associated with longevity across species, from worms to mammals (Fontana et al., 2010).

Key Insight

Fasting creates a coordinated shift in cellular metabolism: mTOR and insulin/IGF-1 signaling decrease while AMPK and sirtuins increase. This shift diverts cellular resources from growth and reproduction toward maintenance and repair, the essence of longevity optimization.

Autophagy: Cellular Housekeeping

Autophagy (from Greek: “self-eating”) is the process by which cells degrade and recycle damaged components, including dysfunctional mitochondria, misfolded proteins, and damaged organelles. Yoshinori Ohsumi received the 2016 Nobel Prize in Physiology or Medicine for elucidating autophagy mechanisms.

Why Autophagy Matters for Aging:

Autophagy dysfunction is a hallmark of aging (Lopez-Otin et al., 2013). As autophagy declines with age:

  • Damaged proteins accumulate
  • Dysfunctional mitochondria persist, producing reactive oxygen species
  • Cellular function deteriorates
  • Senescent cells accumulate

Fasting Activates Autophagy:

In humans, autophagy markers increase significantly after 24-48 hours of fasting, though some autophagy activation begins earlier (Alirezaei et al., 2010). The timeline is not precisely defined, as autophagy rates vary by tissue and individual. Key findings:

  • In mice, neuronal autophagy increases significantly after 24-48 hours of food deprivation (Alirezaei et al., 2010)
  • Liver autophagy in humans increases after overnight fasting and continues to rise with extended fasting (Ezaki et al., 2011)
  • Exercise can accelerate autophagy activation during fasting (He et al., 2012)

Autophagy Timing Uncertainty

Precise autophagy timelines in humans remain uncertain. Claims of “autophagy starting at exactly 16 hours” are oversimplifications. Autophagy is a continuous process that increases gradually with fasting duration, varies by tissue, and is influenced by individual factors including baseline metabolic health and activity level.

Metabolic Switching and Ketosis

Extended fasting depletes liver glycogen stores (typically within 12-36 hours) and shifts the body toward fat oxidation. The liver converts fatty acids into ketone bodies (beta-hydroxybutyrate, acetoacetate, and acetone) that can fuel the brain and other tissues (Anton et al., 2018).

Benefits of Ketosis:

  • Neuroprotection: Beta-hydroxybutyrate (BHB) serves as an efficient brain fuel and acts as a signaling molecule that reduces inflammation and oxidative stress (Newman & Verdin, 2017)
  • BDNF upregulation: Ketones increase brain-derived neurotrophic factor, supporting neuroplasticity (Mattson et al., 2018)
  • Reduced inflammation: BHB inhibits the NLRP3 inflammasome, reducing inflammatory cytokine production (Youm et al., 2015)
  • Histone modification: BHB acts as a histone deacetylase inhibitor, influencing gene expression (Shimazu et al., 2013)

Types of Fasting

Time-Restricted Eating (TRE)

Time-restricted eating confines all caloric intake to a specific window each day, typically 6-12 hours, with the remaining time spent in a fasted state.

Common TRE Protocols:

ProtocolEating WindowFasting PeriodDifficulty
12:1212 hours12 hoursBeginner
14:1010 hours14 hoursEasy
16:88 hours16 hoursModerate
18:66 hours18 hoursChallenging
20:44 hours20 hoursAdvanced
OMAD1-2 hours22-23 hoursVery Advanced

Evidence for TRE:

Panda and colleagues demonstrated that mice fed a high-fat diet within an 8-hour window remained metabolically healthy despite identical caloric intake to mice with 24-hour food access (Hatori et al., 2012). Human studies have shown:

  • 16:8 TRE reduced blood pressure and improved insulin sensitivity in prediabetic men (Sutton et al., 2018)
  • Early time-restricted eating (eating earlier in the day) improved insulin sensitivity, blood pressure, and oxidative stress markers (Sutton et al., 2018)
  • 10-hour TRE improved cardiometabolic health in patients with metabolic syndrome (Wilkinson et al., 2020)

Early vs. Late Eating Windows:

The timing of the eating window matters. Due to circadian rhythms, insulin sensitivity is highest in the morning and declines throughout the day. Early TRE (e.g., 8 AM - 4 PM) appears superior to late TRE for metabolic outcomes (Sutton et al., 2018; Ravussin et al., 2019).

Circadian Alignment

Aligning food intake with daylight hours supports circadian rhythm and metabolic health. The traditional advice to avoid eating late at night has physiological validity. Aim to finish eating at least 3 hours before sleep.

Intermittent Fasting (IF)

Intermittent fasting typically refers to protocols involving complete or near-complete caloric restriction for defined periods, ranging from 24 hours to several days.

Common IF Protocols:

5:2 Diet

  • Eat normally for 5 days per week
  • Restrict calories to 500-600 kcal on 2 non-consecutive days
  • Evidence: Harvie et al. (2011) found 5:2 equivalent to continuous caloric restriction for weight loss and metabolic improvements

Alternate-Day Fasting (ADF)

  • Alternate between normal eating days and fasting days (0-500 kcal)
  • Evidence: Varady et al. (2013) demonstrated weight loss and cardiovascular benefits
  • Challenging for long-term adherence

24-Hour Fasts (Eat-Stop-Eat)

  • Complete fast for 24 hours, once or twice weekly
  • Example: Dinner to dinner, or lunch to lunch
  • Allows some autophagy activation while maintaining social eating patterns

36-Hour Fasts

  • Fast from dinner one day through breakfast two days later
  • Deeper metabolic effects and ketosis
  • Example: Finish dinner Sunday 7 PM, next meal Tuesday 7 AM

Extended Fasting (48-120+ Hours)

Extended fasts of 2-5 days produce more profound metabolic shifts and autophagy activation but require careful consideration and medical supervision.

Physiological Timeline During Extended Fasting:

TimeMetabolic StateKey Events
0-4 hoursFed stateBlood glucose elevated, insulin high
4-8 hoursPost-absorptiveGlucose normalizing, beginning liver glycogen use
8-12 hoursEarly fastingGlycogen depletion begins, gluconeogenesis increases
12-18 hoursFastingGlycogen depleted, fat oxidation increases, ketones appear
18-24 hoursDeep fastingSignificant ketone production, autophagy increasing
24-48 hoursKetosisFull ketosis, enhanced autophagy, growth hormone rises
48-72 hoursDeep ketosisPeak autophagy, significant cellular cleanup, immune regeneration begins
72-120 hoursProlonged fastingStem cell activation, immune system regeneration

Evidence for Extended Fasting:

  • Immune regeneration: Cheng et al. (2014) found that 72-hour fasting cycles promoted hematopoietic stem cell regeneration and reversed immunosenescence in mice, with similar effects suggested in human chemotherapy patients
  • Metabolic resetting: Extended fasting can improve insulin sensitivity and reduce inflammatory markers (Harvie & Howell, 2017)
  • Autophagy: Longer fasts produce more significant autophagy activation, though precise timelines in humans remain under investigation

Extended Fasting Requires Caution

Fasts exceeding 24-48 hours should be approached carefully, ideally with medical supervision. Extended fasting is not appropriate for everyone and carries risks including electrolyte imbalances, muscle loss, refeeding syndrome, and exacerbation of underlying conditions.

Fasting-Mimicking Diet (FMD)

Developed by Valter Longo, the fasting-mimicking diet provides minimal calories (approximately 750-1100 kcal/day) in specific macronutrient ratios designed to maintain fasting physiology while reducing the challenges of complete fasting.

FMD Protocol (ProLon):

DayCaloriesComposition
Day 1~1100 kcal34% carbs, 10% protein, 56% fat
Days 2-5~725-800 kcal47% carbs, 9% protein, 44% fat

Evidence for FMD:

Wei et al. (2017) conducted a randomized controlled trial of three monthly FMD cycles in 100 generally healthy participants:

  • Reduced body weight, trunk fat, and total body fat
  • Lowered blood pressure in hypertensive participants
  • Reduced fasting glucose, IGF-1, and inflammatory markers
  • No adverse effects on lean body mass

Brandhorst et al. (2015) demonstrated in mice that periodic FMD cycles:

  • Extended lifespan
  • Reduced visceral fat
  • Reduced cancer incidence and delayed tumor progression
  • Improved cognitive function
  • Promoted regeneration across multiple organ systems

FMD Accessibility

While commercial FMD products (ProLon) exist, the protocol can be approximated with whole foods: primarily vegetables, nuts, olives, and small amounts of whole grains, emphasizing very low protein and moderate fat/carbohydrate intake. The key is keeping protein very low (approximately 9-10% of calories) to suppress IGF-1 signaling.

Longevity and Health Benefits

Metabolic Health

Insulin Sensitivity and Glucose Regulation:

Fasting consistently improves insulin sensitivity across multiple mechanisms (Patterson & Sears, 2017):

  • Depletes intrahepatic and intramuscular fat that causes insulin resistance
  • Reduces fasting insulin levels, allowing insulin receptors to resensitize
  • Activates AMPK, which enhances glucose uptake
  • Improves mitochondrial function in muscle and liver

Sutton et al. (2018) demonstrated that early TRE improved insulin sensitivity independent of weight loss, suggesting timing effects beyond simple caloric restriction.

Body Composition:

While fasting promotes fat loss, concerns about muscle preservation are valid. Research suggests:

  • Short-term fasting (up to 72 hours) preserves lean mass due to growth hormone elevation and protein-sparing adaptations (Hartman et al., 1992)
  • Extended or repeated fasting without adequate protein intake during eating periods can compromise muscle mass
  • Resistance training during fasting periods helps preserve muscle (Tinsley et al., 2017)

Cardiovascular Health

Fasting improves multiple cardiovascular risk factors:

  • Blood pressure: TRE reduces systolic and diastolic blood pressure (Wilkinson et al., 2020)
  • Lipid profile: Fasting reduces triglycerides and may increase HDL (Varady et al., 2013)
  • Inflammatory markers: Reduced hs-CRP and inflammatory cytokines (Faris et al., 2012)
  • Heart rate variability: Improved HRV suggests enhanced autonomic function

Cognitive Function and Neuroprotection

Fasting and ketosis confer neuroprotective effects through multiple mechanisms (Mattson et al., 2018):

  • BDNF elevation: Fasting increases brain-derived neurotrophic factor, supporting neuroplasticity, learning, and memory
  • Ketone fuel: BHB provides efficient fuel for neurons and has neuroprotective properties
  • Reduced inflammation: Lower neuroinflammation may slow cognitive decline
  • Autophagy: Clearing damaged proteins may reduce risk of neurodegenerative diseases

Animal studies consistently show fasting protects against Alzheimer’s and Parkinson’s disease pathology (Mattson et al., 2018). Human evidence is limited but suggests cognitive benefits, particularly in aging populations.

Cancer and Cellular Health

Fasting may reduce cancer risk and improve outcomes through several mechanisms (Nencioni et al., 2018):

  • Differential stress resistance: Normal cells enter protective mode during fasting, while cancer cells remain vulnerable to stress
  • IGF-1 reduction: Lower IGF-1 signaling reduces cancer cell proliferation
  • Autophagy: Clearing damaged cells may prevent malignant transformation
  • Reduced inflammation and oxidative stress: Lower cancer-promoting environment

Clinical trials are investigating fasting alongside chemotherapy, with preliminary evidence suggesting improved tolerance and potentially enhanced efficacy (de Groot et al., 2015).

Cancer and Fasting

While preclinical evidence is promising, fasting during cancer treatment should only be undertaken under oncologist supervision. Malnutrition is a concern in cancer patients, and fasting protocols must be carefully individualized.

Inflammation and Immune Function

Fasting produces anti-inflammatory effects through (Jordan et al., 2019):

  • Reduced inflammatory cytokine production (IL-6, TNF-alpha, IL-1beta)
  • BHB inhibition of NLRP3 inflammasome
  • Immune cell changes including reduced inflammatory monocytes
  • Gut microbiome modifications favoring anti-inflammatory species

Periodic extended fasting may “reset” the immune system by clearing damaged immune cells and promoting stem cell-based regeneration (Cheng et al., 2014).

Evidence-Based Protocols

Protocol 1: 16:8 Time-Restricted Eating (Foundation)

Who it’s for: Beginners, those seeking sustainable metabolic benefits

The Protocol:

  1. Eating window: 8 hours (e.g., 10 AM - 6 PM or 12 PM - 8 PM)
  2. Fasting window: 16 hours (including sleep)
  3. Frequency: Daily
  4. During fasting: Water, black coffee, plain tea permitted

Implementation:

  • Week 1-2: Start with 12:12, skip breakfast or move it later
  • Week 3-4: Extend to 14:10
  • Week 5+: Achieve 16:8

Expected Benefits:

  • Improved insulin sensitivity
  • Modest fat loss
  • Circadian rhythm alignment
  • Sustainable long-term practice

Protocol 2: 18:6 or 20:4 Compressed Eating Window

Who it’s for: Intermediate practitioners, those seeking deeper metabolic effects

The Protocol:

  1. Eating window: 4-6 hours (e.g., 12 PM - 6 PM)
  2. Fasting window: 18-20 hours
  3. Frequency: Daily or 5-6 days per week
  4. Meals: 1-2 substantial meals during the window

Considerations:

  • Ensure adequate protein and nutrition in compressed window
  • May require larger meal sizes
  • Pair with resistance training to preserve muscle
  • Monitor energy levels and adjust as needed

Protocol 3: OMAD (One Meal a Day)

Who it’s for: Experienced fasters, those highly adapted to fasting

The Protocol:

  1. Eating window: 1-2 hours
  2. Fasting window: 22-23 hours
  3. Frequency: Daily or several days per week
  4. The meal: Large, nutrient-dense, protein-adequate

Considerations:

  • Challenging to meet nutritional needs in one meal
  • Risk of undereating protein and micronutrients
  • May affect social eating and lifestyle
  • Not recommended for those new to fasting or with history of eating disorders

Protocol 4: Weekly 24-Hour Fast

Who it’s for: Those wanting periodic deeper fasts without extended duration

The Protocol:

  1. Timing: Once weekly, dinner to dinner or lunch to lunch
  2. Duration: 24 hours
  3. During fast: Water, electrolytes, black coffee, tea
  4. Break-fast meal: Moderate portion, easily digestible foods

Example Schedule:

  • Sunday dinner at 6 PM
  • No food Monday
  • Break fast Monday 6 PM with dinner

Protocol 5: Monthly 48-72 Hour Fast

Who it’s for: Advanced practitioners seeking significant autophagy activation

The Protocol:

  1. Frequency: Once per month
  2. Duration: 48-72 hours
  3. Preparation: Reduce carbohydrates 2-3 days before to ease transition
  4. During fast: Water, electrolytes (sodium, potassium, magnesium), bone broth optional
  5. Breaking fast: Gentle refeeding protocol (see below)

Considerations:

  • First extended fast should be supervised or undertaken cautiously
  • Monitor for signs of distress
  • Some physical activity is fine; avoid intense exercise
  • Mental clarity often improves after initial 24-36 hours

Protocol 6: Quarterly 5-Day Fasting-Mimicking Diet

Who it’s for: Those seeking extended fast benefits with easier adherence and safety

The Protocol:

  1. Frequency: Every 1-3 months
  2. Duration: 5 consecutive days
  3. Calories: Day 1: 1100 kcal; Days 2-5: 750-800 kcal
  4. Macros: Very low protein (9-10%), moderate carbs (45-47%), moderate fat (44-56%)

DIY FMD Food Suggestions:

  • Vegetable soups (low sodium)
  • Olives and olive oil
  • Small portions of nuts
  • Leafy greens and non-starchy vegetables
  • Herbal teas
  • Avoid: Protein sources, high-glycemic carbohydrates

Who Should and Should Not Fast

Good Candidates for Fasting

  • Generally healthy adults with stable weight
  • Those with metabolic syndrome seeking to improve insulin sensitivity
  • Overweight or obese individuals (under appropriate guidance)
  • Those comfortable with hunger and meal flexibility
  • Individuals with established healthy eating patterns

Contraindications

Who Should NOT Fast

Absolute Contraindications:

  • Pregnant or breastfeeding women
  • Children and adolescents (growth requirements)
  • Type 1 diabetics (without careful medical supervision)
  • Those with active eating disorders or history of anorexia/bulimia
  • Severely underweight individuals (BMI < 18.5)
  • Those taking medications requiring food for absorption or blood sugar management

Relative Contraindications (Medical Supervision Required):

  • Type 2 diabetics on insulin or sulfonylureas (hypoglycemia risk)
  • Those with gout (fasting can trigger attacks)
  • Those with gallstones
  • Elderly or frail individuals
  • Those with significant chronic illness
  • Athletes during heavy training periods

Special Populations

Women: Some women experience menstrual irregularities or hormonal disruption with aggressive fasting protocols. Women may benefit from:

  • Shorter fasting windows (14:10 rather than 18:6)
  • Avoiding fasting during the luteal phase (latter half of menstrual cycle)
  • Not fasting on consecutive days
  • Monitoring for signs of hormonal disruption

Older Adults: Adults over 65 face competing concerns:

  • Sarcopenia risk (muscle loss) with extended fasting
  • Reduced autophagy with aging (fasting may be more beneficial)
  • Higher protein needs
  • Recommendation: Shorter TRE windows (12-14 hours) with adequate protein; extended fasts only with medical supervision

Breaking a Fast Properly

How you end a fast matters, particularly for extended fasts. Improper refeeding can cause digestive distress and, in extreme cases, refeeding syndrome (dangerous electrolyte shifts).

Breaking Short Fasts (16-24 hours)

No special precautions required. Resume normal eating with any nutritious meal.

Breaking Extended Fasts (48+ hours)

Phase 1: First Meal (Hours 0-2)

  • Small portion (200-400 kcal)
  • Easily digestible foods
  • Low fiber, low fat
  • Examples: Bone broth, soft-cooked eggs, avocado, small portion of fish

Phase 2: Second Meal (Hours 4-8)

  • Moderate portion
  • Add protein and vegetables
  • Still avoid large amounts of fiber or hard-to-digest foods
  • Examples: Salmon with steamed vegetables, chicken soup with vegetables

Phase 3: Return to Normal (Day 2+)

  • Gradually increase portion sizes
  • Reintroduce fibrous vegetables and normal foods
  • Resume regular eating pattern

Refeeding Syndrome

Refeeding syndrome is rare but serious, occurring primarily after prolonged starvation or very extended fasts (7+ days). It involves dangerous shifts in electrolytes (phosphate, potassium, magnesium) when eating resumes. Extended fasts beyond 5-7 days should be medically supervised, with electrolyte monitoring.

Foods to Avoid When Breaking Extended Fasts

  • Large portions
  • High-fiber vegetables (raw broccoli, raw cabbage)
  • Nuts and seeds in large quantities
  • Dairy (can cause digestive distress)
  • Processed foods and sugars
  • Alcohol

Fasting and Exercise Timing

The interaction between fasting and exercise is nuanced and depends on goals and training type.

Fasted Exercise: Benefits and Considerations

Potential Benefits:

  • Enhanced fat oxidation during low-intensity exercise (Vieira et al., 2016)
  • Greater metabolic flexibility with adaptation
  • Improved insulin sensitivity post-exercise
  • Some evidence for enhanced mitochondrial adaptations (Van Proeyen et al., 2011)

Considerations:

  • Performance may decrease for high-intensity efforts
  • Glycogen-depleted muscles cannot sustain prolonged high-intensity work
  • Risk of muscle breakdown if protein intake is inadequate
  • Some individuals feel weak or lightheaded

Practical Recommendations

Zone 2 Cardio and Fasting: Low-intensity aerobic exercise is well-suited to the fasted state. Fat oxidation is maximized, and glycogen demands are low. Many practitioners perform morning Zone 2 sessions while fasted with good results.

Resistance Training and Fasting: More complex. While fasted training is possible:

  • Consume protein within 1-2 hours post-workout to maximize muscle protein synthesis
  • Consider training near the end of the fasting window, with protein intake shortly after
  • Some evidence suggests post-workout protein timing matters less than total daily intake (Schoenfeld et al., 2013), but proximity to training remains prudent

High-Intensity Training: Not ideal in a deeply fasted state. Performance suffers without glycogen availability. Options:

  • Train during eating window
  • Train near end of fast and eat immediately after
  • Use targeted ketone supplements (advanced)

For 16:8 TRE practitioners:

Training TypeTimingPost-Workout
Zone 2 cardioFasted morningCan wait until eating window
Resistance trainingLate morning/early afternoonBreak fast with protein-rich meal
HIIT/High-intensityDuring eating windowConsume carbs + protein after

Listen to Your Body

Individual responses vary. Some thrive training fasted; others feel terrible. Experiment with training timing and assess energy, performance, and recovery. If performance consistently suffers, adjust the approach.

Tracking and Measuring Benefits

Subjective Markers

Monitor these during and after fasting protocols:

  • Mental clarity and focus
  • Energy levels and stability
  • Hunger patterns (should decrease with adaptation)
  • Sleep quality
  • Mood and irritability
  • Digestive function

Objective Biomarkers

Glucose Monitoring:

Continuous glucose monitors or fingerstick glucometers provide insight into metabolic state:

  • Fasting glucose: Should decrease with regular fasting practice
  • Glucose variability: Should decrease
  • Time in optimal range (70-100 mg/dL): Should increase
  • Post-meal glucose spikes: Should blunt with improved insulin sensitivity

Ketone Measurement:

Blood or breath ketone meters confirm metabolic switching:

  • Nutritional ketosis: 0.5-3.0 mmol/L beta-hydroxybutyrate
  • Light ketosis typically begins: 12-18 hours fasting
  • Moderate ketosis: 24-48 hours
  • Deep ketosis: 48+ hours
Ketone Level (BHB)State
< 0.5 mmol/LNot in ketosis
0.5-1.0 mmol/LLight ketosis
1.0-3.0 mmol/LOptimal ketosis
3.0-5.0 mmol/LDeep ketosis (extended fast)
> 5.0 mmol/LStarvation ketosis (not target)

Blood Work:

Track these markers every 3-6 months:

  • Fasting insulin (target: < 5 uIU/mL)
  • Fasting glucose (target: 70-90 mg/dL)
  • HbA1c (target: < 5.4%)
  • Triglycerides (target: < 100 mg/dL, ideally < 70)
  • hs-CRP (target: < 1.0 mg/L)
  • IGF-1 (context-dependent; lower associated with longevity)

Autophagy Markers:

Direct autophagy measurement in humans is challenging outside research settings. Indirect indicators:

  • Extended fasting duration (24+ hours)
  • Ketone elevation (indicates metabolic shift associated with autophagy)
  • Research markers (not clinically available): LC3-II, p62/SQSTM1

Body Composition

Track with DEXA scans or reliable methods:

  • Maintain or increase lean body mass
  • Reduce visceral adipose tissue
  • Improve body fat percentage

Evidence Matrix

SourceVerdictNotes
Valter Longo (USC)Strongly RecommendsDeveloper of FMD; advocates periodic prolonged fasting for longevity
Satchin Panda (Salk)Strongly RecommendsTime-restricted eating research; emphasizes circadian alignment
Peter AttiaRecommends with NuanceTRE useful; concerns about muscle loss with extended fasting in older adults
Huberman LabRecommendsEmphasizes TRE, circadian timing, and individual variation
Rhonda PatrickRecommendsFocus on autophagy, metabolic health; cautions about protein timing
Clinical EvidenceModerate-StrongStrong for metabolic markers; longevity evidence primarily preclinical

Key Studies:

  • Hatori et al. (2012): TRE protected mice from obesity and metabolic disease despite high-fat diet
  • Sutton et al. (2018): Early TRE improved insulin sensitivity independent of weight loss in prediabetic men
  • Wei et al. (2017): FMD reduced markers of aging, diabetes, and cardiovascular disease in humans
  • Cheng et al. (2014): Prolonged fasting cycles promoted immune regeneration through stem cell activation
  • Mattson et al. (2018): Comprehensive review of fasting effects on brain health and neuroprotection
  • Wilkinson et al. (2020): 10-hour TRE improved cardiometabolic health in metabolic syndrome patients

Common Pitfalls

Mistakes to Avoid

  1. Starting too aggressively: Jumping into extended fasts without adaptation causes misery and failure. Progress gradually from 12:12 to 16:8 over weeks.
  2. Inadequate hydration and electrolytes: Fasting increases water and electrolyte loss. Supplement sodium, potassium, and magnesium during extended fasts.
  3. Neglecting protein: Chronic undereating of protein accelerates muscle loss. Ensure adequate protein (1.2-1.6 g/kg) during eating windows.
  4. Using fasting to justify poor food choices: Fasting does not offset a junk food diet. Combine fasting with nutrient-dense whole foods.
  5. Ignoring contraindications: Fasting is not for everyone. Pregnant women, those with eating disorders, and certain medical conditions should not fast.
  6. Obsessing over exact timings: “Autophagy starts at exactly 16 hours” is oversimplified. Focus on consistent practice rather than arbitrary cutoffs.
  7. Fasting while highly stressed: Chronic stress plus fasting stress can backfire. Address stress before adding fasting.
  8. Excessive exercise during extended fasts: Light activity is fine; intense training without fuel depletes muscle and impairs recovery.
  9. Breaking extended fasts improperly: Large meals after extended fasts cause digestive distress. Refeed gradually.
  10. Making fasting an identity: Fasting is a tool, not a lifestyle. Flexibility and sustainability matter more than rigid adherence.

Implementation Checklist

Week 1-2: Baseline and Preparation

  • Establish consistent whole-food diet first
  • Track current eating patterns and meal timing
  • Get baseline blood work (fasting glucose, insulin, lipids, hs-CRP)
  • Begin 12:12 TRE (e.g., 8 AM - 8 PM eating window)

Week 3-4: Establish TRE Foundation

  • Extend to 14:10, then 16:8 if comfortable
  • Eliminate snacking between meals
  • Notice hunger patterns and adaptation
  • Maintain hydration (water, black coffee, tea during fast)

Week 5-8: Optimize and Personalize

  • Find sustainable eating window that fits lifestyle
  • Consider circadian alignment (earlier eating)
  • Track subjective markers (energy, clarity, hunger)
  • Optional: Try first 24-hour fast

Month 3+: Advanced Protocols

  • Consider monthly 24-48 hour fast or FMD
  • Repeat blood work and compare to baseline
  • Track body composition changes
  • Adjust protocol based on results and lifestyle

Ongoing Maintenance

  • Maintain consistent TRE practice (16:8 or similar)
  • Periodic extended fasts or FMD quarterly
  • Annual blood work to track metabolic markers
  • Adjust as goals and life circumstances change

Connected Concepts

  • Diet: Fasting builds on quality nutrition; what you eat matters as much as when
  • Sleep: Align eating window with circadian rhythm; stop eating 3+ hours before bed
  • Exercise: Coordinate training timing with fasting; prioritize protein post-workout
  • Supplement Basics: Electrolytes during extended fasts; some supplements break fasts
  • Cold Exposure: Stacking stressors may amplify or compete; individualize timing
  • Heat Exposure: Sauna during fasting requires extra attention to hydration
  • Rapamycin: Pharmacological mTOR inhibition; fasting provides similar pathway modulation
  • CGM Protocols: Track glucose response to fasting and eating windows
  • Advanced Lipids: Fasting improves lipid markers; track triglycerides and HDL

Concepts

  • Autophagy: Fasting’s primary cellular cleanup mechanism
  • mTOR: Inhibited during fasting, allowing repair processes
  • AMPK: Activated during energy deficit, promoting metabolic health
  • Sirtuins: NAD+-dependent enzymes activated by fasting
  • Insulin: Decreases during fasting, improving sensitivity
  • Glucose: Stabilizes with fasting practice and TRE
  • IGF-1: Reduced during fasting, associated with longevity
  • Circadian Rhythm: Align eating with daylight for optimal metabolic effects
  • Mitochondria: Fasting promotes mitochondrial biogenesis and quality control

Biomarkers

Further Reading

Books:

  • “The Longevity Diet” by Valter Longo: Research-based fasting protocols from leading longevity scientist
  • “The Complete Guide to Fasting” by Jason Fung: Practical guide to fasting implementation
  • “Lifespan” by David Sinclair: Context for fasting within broader longevity framework
  • “The Circadian Code” by Satchin Panda: Time-restricted eating and circadian biology

Podcasts:

  • The Drive (Peter Attia): Episodes with Valter Longo and Satchin Panda on fasting
  • Huberman Lab: Episodes on fasting, time-restricted eating, and metabolic health
  • FoundMyFitness (Rhonda Patrick): Deep dives on fasting mechanisms and research

Research:

  • Valter Longo Lab publications (University of Southern California)
  • Satchin Panda Lab publications (Salk Institute)
  • Mark Mattson’s fasting and brain health research (NIH)

References

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Last updated: 2026-01-01

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