Intermittent fasting (IF) is a flexible dietary approach that alternates between fasting and eating periods, with common protocols including time-restricted eating, alternate-day fasting, and the 5:2 diet. Unlike traditional calorie-restriction diets, IF focuses on meal timing rather than food choices.
This brief review summarizes evidence from human studies showing that IF can improve insulin sensitivity, reduce inflammation, enhance brain function, and potentially extend lifespan, highlighting its promise in promoting metabolic health and preventing disease.
1. Introduction to intermittent fasting
Intermittent fasting (IF) is an eating pattern that alternates between periods of fasting and eating. This practice has gained significant attention in recent years due to its potential health benefits. However, intermittent fasting is not a new concept; it has deep historical roots and has been practiced for centuries across various cultures and religions.
1.1. Historical context
Fasting has been a part of human history for millennia, often intertwined with cultural, religious, and spiritual practices. Ancient civilizations, including the Greeks, Romans, and Egyptians, practiced fasting for health and purification. Hippocrates, the father of modern medicine, advocated for fasting as a treatment for certain ailments (Hippocrates, 400 BCE).
Religious traditions such as Islam (Ramadan), Christianity (Lent), and Judaism (Yom Kippur) have long incorporated fasting as a means of spiritual discipline and self-control (Patterson & Sears, 2017).
Intermittent fasting as a structured dietary approach, however, gained scientific traction in the 20th century. Early animal studies in the 1930s and 1940s demonstrated that calorie restriction could extend lifespan and improve health outcomes (McCay et al., 1935). These findings laid the groundwork for modern research on intermittent fasting and its effects on human health.
1.2. Modern practice of intermittent fasting
Intermittent fasting encompasses several methods, each with its own fasting and eating windows (Mattson et al., 2017). The most popular approaches include:
• Time-Restricted Feeding (TRF). This method involves eating within a specific window each day, typically 6-8 hours, and fasting for the remaining 16-18 hours. For example, the 16:8 method is a common TRF approach (Patterson & Sears, 2017).
• Alternate-Day Fasting (ADF). This approach alternates between days of normal eating and days of severe calorie restriction (e.g., 500 calories) or complete fasting (Varady et al., 2013).
• 5:2 Diet. In this method, individuals eat normally for five days of the week and restrict calorie intake to 500-600 calories on the remaining two days (Harvie et al., 2011).
2. Mechanisms of action
Intermittent fasting exerts its effects through several interconnected mechanisms:
2.1. Metabolic switching and ketogenesis
• Glycogen depletion: during fasting, glycogen stores in the liver are depleted, prompting the body to break down fat into free fatty acids and glycerol.
• Ketone production: in the liver, fatty acids are converted into ketone bodies (e.g., beta-hydroxybutyrate), which serve as an alternative energy source for the brain and muscles.
• Insulin sensitivity: ketogenesis is associated with reduced insulin levels and improved insulin sensitivity, which helps regulate blood sugar and reduce the risk of type 2 diabetes.
Clinical evidence: a 2018 randomized controlled trial (RCT) by Sutton et al., demonstrated that early time-restricted feeding (eTRF) improved insulin sensitivity and reduced fasting insulin levels in prediabetic men, even without weight loss (Sutton et al., 2018).
2.2. Autophagy and cellular repair
• Activation of autophagy: during fasting, the reduction in nutrient availability activates autophagy through pathways involving mTOR (mechanistic target of rapamycin) and AMPK (AMP-activated protein kinase).
• Cellular detoxification: autophagy clears out dysfunctional mitochondria and protein aggregates, reducing oxidative stress and inflammation.
Clinical evidence: a 2021 study by Pietrocola et al., found that fasting-mimicking diets upregulated autophagy-related genes in humans, suggesting a potential role in cellular repair and longevity (Pietrocola et al., 2021).
2.3. Hormonal regulation
• Insulin: fasting lowers insulin levels, improving insulin sensitivity and reducing the risk of metabolic syndrome.
• Human Growth Hormone (HGH): fasting increases HGH secretion, which supports fat metabolism, muscle preservation, and tissue repair.
• Norepinephrine: fasting enhances the release of norepinephrine, a hormone that boosts metabolism and fat oxidation.
Clinical evidence: A 2017 RCT by Antoni et al., investigated the effects of time-restricted eating on hormonal profiles in overweight adults. The study found significant reductions in fasting insulin levels and increases in HGH, supporting the role of IF in hormonal regulation (Antoni et al., 2017).
2.4. Gene expression and longevity pathways
• Sirtuins: fasting upregulates sirtuins (e.g., SIRT1), which play a role in DNA repair, inflammation reduction, and mitochondrial function.
• FOXO transcription factors: these proteins regulate genes involved in antioxidant defense, apoptosis, and cellular repair.
• Nrf2 pathway: fasting activates the Nrf2 pathway, which enhances the expression of antioxidant enzymes.
Clinical evidence: a 2017 study by Wei et al., demonstrated that fasting-mimicking diets upregulated sirtuin and FOXO pathways in humans, leading to reduced markers of aging and improved metabolic health (Wei et al., 2017).
2.5. Inflammation and oxidative stress reduction
• Reduction in pro-inflammatory cytokines: fasting lowers levels of inflammatory markers like IL-6, TNF-alpha, and CRP.
• Enhanced antioxidant defenses: fasting increases the production of endogenous antioxidants, such as glutathione and superoxide dismutase.
Clinical evidence: A 2021 RCT by Cienfuegos et al., found that alternate-day fasting significantly reduced markers of inflammation and oxidative stress in obese adults, highlighting the anti-inflammatory effects of IF (Cienfuegos et al., 2021).
2.6. Gut microbiota modulation
• Microbial diversity: fasting increases microbial diversity, which is associated with improved metabolic health.
• Short-Chain Fatty Acids (SCFAs): fasting enhances the production of SCFAs, which have anti-inflammatory and metabolic benefits.
Clinical evidence: a 2020 study by Li et al., demonstrated that time-restricted eating altered the gut microbiota composition in overweight adults, leading to improved metabolic outcomes (Li et al., 2020).
2.7. Neuroprotection and brain health
• Increased BDNF: Fasting boosts brain-derived neurotrophic factor (BDNF), which supports neuron growth and cognitive function.
• Reduced neuroinflammation: Fasting lowers inflammation in the brain, protecting against neurodegenerative diseases like Alzheimer’s and Parkinson’s.
Clinical evidence: a 2018 study by Mattson et al., reviewed the effects of IF on brain health, citing human studies that showed improvements in cognitive function and reduced markers of neuroinflammation (Mattson et al., 2018).
3. Health benefits of intermittent fasting
3.1. Weight loss and fat reduction
• Time-restricted eating (TRE) and weight loss: a 2020 RCT by Cienfuegos et al., compared time-restricted eating (TRE) with a 16:8 fasting window to a control group. The TRE group lost significantly more weight (3.3% of body weight) and reduced visceral fat compared to the control group over 12 weeks (Cienfuegos et al., 2020).
• Alternate-day fasting: a 2017 RCT by Trepanowski et al., found that alternate-day fasting (ADF) resulted in a 6% reduction in body weight over 12 months, comparable to daily calorie restriction (Trepanowski et al., 2017).
3.2. Improved metabolic health
• Insulin sensitivity: a 2018 RCT by Sutton et al., demonstrated that early time-restricted feeding (eTRF) improved insulin sensitivity by 11% and reduced fasting insulin levels in prediabetic men, even without weight loss (Sutton et al., 2018).
• HbA1c reduction: the PROFAST trial (Tay et al., 2020) showed that intermittent fasting reduced HbA1c levels in individuals with prediabetes, highlighting its potential for glycemic control (Tay et al., 2020).
• Lipid profile: a 2021 RCT by Gabel et al., found that TRE improved LDL cholesterol, triglycerides, and HDL cholesterol in obese adults, reducing cardiovascular risk factors (Gabel et al., 2021).
3.3. Cardiovascular health
• Blood pressure: a 2020 RCT by Wilkinson et al., found that TRE reduced systolic blood pressure by 7 mmHg and diastolic blood pressure by 4 mmHg in hypertensive patients over 12 weeks (Wilkinson et al., 2020).
• Inflammation: a 2021 RCT by Cienfuegos et al., demonstrated that alternate-day fasting reduced markers of inflammation, such as C-reactive protein (CRP) and interleukin-6 (IL-6), in obese adults (Cienfuegos et al., 2021).
3.4. Brain function and neuroprotection
• Cognitive performance: a 2019 RCT by Mattson et al., found that IF improved memory, attention, and executive function in older adults, likely due to increased brain-derived neurotrophic factor (BDNF) levels (Mattson et al., 2019).
• Neuroinflammation: a 2020 study by Phillips et al., showed that IF reduced markers of neuroinflammation in individuals with mild cognitive impairment, suggesting a protective effect against Alzheimer’s disease (Phillips et al., 2019).
3.5. Psychological well-being
• Hosseini et al., (2024) examined how fasting diets influence mindful eating, sleep, mood, and overall well-being. The key findings were that fasting was associated with enhanced awareness of hunger and satiety, improved sleep quality, and better mood, collectively contributing to increased overall well-being.
3.6. Longevity and cellular health
• Autophagy and cellular repair: a 2021 study by Pietrocola et al., found that fasting-mimicking diets upregulated autophagy-related genes in humans, supporting cellular repair and longevity (Pietrocola et al., 2021).
• Oxidative stress: a study by Brandhorst et al., (2015) found that fasting-mimicking diets (FMDs) in humans reduced markers of oxidative stress and inflammation while increasing levels of protective proteins like PKA and AMPK. These pathways are associated with improved stress resistance and longevity.
• Mitochondrial resilience: Mattson et al., (2017) highlighted that intermittent fasting enhances mitochondrial resilience, making cells more efficient at producing energy and less prone to damage.
4. Intermittent fasting and probiotic supplementation
The PROFAST trial investigated the effects of intermittent fasting combined with Lacticaseibacillus rhamnosus HN001 probiotic on individuals with prediabetes. In this randomized, double-blinded study published in Nutrients (Tay et al., 2020), 33 participants with HbA1c levels of 40–50 mmol/mol underwent intermittent fasting (2 days per week of calorie restriction to 600–650 kcal/day) and were assigned to either a probiotic or placebo group for 12 weeks.
The primary outcome was a change in HbA1c, with secondary outcomes including anthropometry, body composition, glucoregulatory markers, and psychological factors. Of the 26 completers, both groups showed significant reductions in HbA1c (from 43 ± 2.7 mmol/mol to 41 ± 2.3 mmol/mol, p < 0.001) and an average 5% weight loss. However, no significant between-group differences were observed in primary or secondary outcomes, except for improvements in psychological functions, specifically social functioning (p = 0.050) and mental health (p = 0.007), in the probiotic group.
5. Safety and considerations
While intermittent fasting is generally safe for healthy individuals, it may not be suitable for everyone. Potential risks and considerations include:
• Nutrient deficiency: Prolonged fasting without proper nutrient intake can lead to deficiencies in vitamins and minerals.
• Eating disorders: intermittent fasting may trigger disordered eating patterns in susceptible individuals, particularly those with a history of anorexia or bulimia.
• Pregnancy and lactation: fasting is not recommended for pregnant or breastfeeding women due to increased nutritional demands.
• Medications: individuals taking medications, especially for diabetes or blood pressure, should consult a healthcare provider before starting IF, as fasting can alter drug efficacy.
6. Practical recommendations
For those interested in trying intermittent fasting, the following tips can help ensure success:
1. Start gradually: begin with a shorter fasting window (e.g., 12 hours) and gradually increase it.
2. Stay hydrated: drink plenty of water during fasting periods.
3. Focus on nutrient-dense foods: prioritize whole, unprocessed foods during eating windows to meet nutritional needs.
4. Monitor health markers: regularly check blood sugar, LDL cholesterol, and blood pressure levels to ensure safety.
5. Consult a professional: Seek guidance from a healthcare provider or nutritionist, especially if you have underlying health conditions.
7. Provisional conclusions
Intermittent fasting is a dietary practice with a rich historical background and growing scientific support. It can offer potential health benefits, that include weight loss, improved metabolic and cardiovascular health, enhanced brain function, psychological well-being, and potential longevity.
While further research is needed to fully understand its long-term effects, IF represents a promising dietary strategy for improving overall health and preventing chronic diseases. However, it is important to approach fasting with caution, particularly for individuals with certain medical conditions or nutritional needs.
Dario Dongo
References
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Dario Dongo, lawyer and journalist, PhD in international food law, founder of WIISE (FARE - GIFT - Food Times) and Égalité.
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