Effects of Intermittent Fasting on Health, Aging, and Disease

The New England Journal of Medicine

December 26, 2019; Vol. 381; No. 26; pp. 2541-2551

Rafael de Cabo, PhD and Mark P. Mattson, PhD: From the National Institutes of Health, and the Department of Neuroscience, Johns Hopkins University School of Medicine. This study cites 80 references. 


In recent years, the concept of intermittent fasting has gained significant attention for its potential health benefits beyond mere calorie restriction. While initially, it was believed that the positive effects of calorie restriction were primarily due to a reduction in free radical production, emerging research suggests that intermittent fasting triggers a cascade of adaptive cellular responses, influencing various aspects of metabolism and promoting overall well-being.

  • Metabolic Switching and Ketogenesis:
    • Calorie restriction diets often involve fasting for extended periods, allowing for metabolic switching from glucose to ketones derived from adipose cells. This process not only fuels cells during fasting but also induces systemic and cellular responses that extend into the fed state, enhancing mental and physical performance and disease resistance.
  • Cellular Responses Beyond Free Radical Reduction:
    • Contrary to earlier beliefs, the health benefits of intermittent fasting are not solely attributed to reduced free-radical production or weight loss. Instead, intermittent fasting engages evolutionarily conserved cellular responses, improving glucose regulation, stress resistance, and suppressing inflammation.
  • Cellular Pathways Activated During Fasting:
    • Fasting activates cellular pathways that enhance intrinsic defenses against oxidative and metabolic stress, facilitating the removal or repair of damaged molecules. This contrasts with the typical three-meals-a-day pattern that most people follow, where intermittent fasting rarely occurs.
  • Disease-Modifying Efficacy:
    • Studies consistently highlight the disease-modifying efficacy of intermittent fasting across various chronic disorders, including obesity, diabetes, cardiovascular diseases, cancers, and neurodegenerative brain diseases.
  • Anti-Aging and Disease Reversal:
    • Intermittent fasting is shown to slow or reverse aging and disease processes, triggering a range of beneficial effects such as enhanced cognition, improved insulin sensitivity, and prevention of obesity.
  • Key Triggers of Intermittent Fasting:
    • Intermittent fasting triggers low levels of amino acids, glucose, and insulin, down-regulates insulin-IGF-1, inhibits protein synthesis, stimulates autophagy, and enhances mitochondrial biogenesis.
  • Adaptations in Human Evolution:
    • Reflecting on our evolutionary history, intermittent fasting aligns with the lifestyle of our ancestors who did not consume three regularly spaced, large meals each day. Repeated exposure to fasting periods led to lasting adaptive responses, conferring resistance to subsequent challenges.


Intermittent fasting emerges as a powerful and versatile approach with broad-spectrum benefits for health conditions such as obesity, diabetes mellitus, cardiovascular diseases, cancers, and neurologic disorders. As the evidence continues to accumulate, incorporating intermittent fasting prescriptions into early interventions for patients at risk or experiencing chronic conditions may pave the way for a paradigm shift in healthcare practices. Embracing the principles of intermittent fasting opens new possibilities for optimizing health and well-being in a world dominated by constant access to food.