The New England Journal of Medicine allows anyone who signs up to read three free articles a month. Make Rafael de Cabo and Mark Mattson’s review article “Effects of Intermittent Fasting on Health, Aging, and Disease” one of your three articles this month. It could add years to your life. “Intermittent fasting” means having periods of, say 18 hours or more without food, or with very little food. As Rafael and Mark write:

… the three most widely studied intermittent-fasting regimens are alternate-day fasting, 5:2 intermittent fasting (fasting 2 days each week), and daily time-restricted feeding.

Let me give a few other quotations to convince you to read Rafael and Mark’s article, with my labels in bold:

• Humans, like other animals, have evolved to function well with intermittent fasting: Studies in animals and humans have shown that many of the health benefits of intermittent fasting are not simply the result of reduced free-radical production or weight loss. Instead, intermittent fasting elicits evolutionarily conserved, adaptive cellular responses that are integrated between and within organs in a manner that improves glucose regulation, increases stress resistance, and suppresses inflammation. 

• Fasting between 12 and 24 hours has big effects on ketosis: During periods of fasting, triglycerides are broken down to fatty acids and glycerol, which are used for energy. The liver converts fatty acids to ketone bodies, which provide a major source of energy for many tissues, especially the brain, during fasting (Figure 2). In the fed state, blood levels of ketone bodies are low, and in humans, they rise within 8 to 12 hours after the onset of fasting, reaching levels as high as 2 to 5 mM by 24 hours. … The timing of this response gives some indication of the appropriate periods for fasting in intermittent-fasting regimens.

• Ketones are powerful signaling molecules: Ketone bodies are not just fuel used during periods of fasting; they are potent signaling molecules with major effects on cell and organ functions.

• We are not evolved for a sedentary life with 3 meals a day: In contrast to people today, our human ancestors did not consume three regularly spaced, large meals, plus snacks, every day, nor did they live a sedentary life. 

• Fasting is a time for repair and refurbishing of cells: Cells respond to intermittent fasting by engaging in a coordinated adaptive stress response that leads to increased expression of antioxidant defenses, DNA repair, protein quality control, mitochondrial biogenesis and autophagy, and down-regulation of inflammation (Figure 3). These adaptive responses to fasting and feeding are conserved across taxa.

• Fasting not only leads to weight loss, it augments the benefits from weight loss: In humans, intermittent-fasting interventions ameliorate obesity, insulin resistance, dyslipidemia, hypertension, and inflammation. Intermittent fasting seems to confer health benefits to a greater extent than can be attributed just to a reduction in caloric intake. In one trial, 16 healthy participants assigned to a regimen of alternate-day fasting for 22 days lost 2.5% of their initial weight and 4% of fat mass, with a 57% decrease in fasting insulin levels. In two other trials, overweight women (approximately 100 women in each trial) were assigned to either a 5:2 intermittent-fasting regimen or a 25% reduction in daily caloric intake. The women in the two groups lost the same amount of weight during the 6-month period, but those in the group assigned to 5:2 intermittent fasting had a greater increase in insulin sensitivity and a larger reduction in waist circumference.

• Fasting improves athletic performance in mice and doesn’t lead to any loss of muscle mass if you work out: In animals and humans, physical function is improved with intermittent fasting. For example, despite having similar body weight, mice maintained on alternate-day fasting have better running endurance than mice that have unlimited access to food. Balance and coordination are also improved in animals on daily time-restricted feeding or alternate-day fasting regimens. Young men who fast daily for 16 hours lose fat while maintaining muscle mass during 2 months of resistance training.

• Fasting is anti-cancer: … numerous studies in animals have shown that daily caloric restriction or alternate-day fasting reduces the occurrence of spontaneous tumors during normal aging in rodents and suppresses the growth of many types of induced tumors while increasing their sensitivity to chemotherapy and irradiation. Similarly, intermittent fasting is thought to impair energy metabolism in cancer cells, inhibiting their growth and rendering them susceptible to clinical treatments.

• Fasting looks like it is anti-Alzheimer’s and anti-Parkinson’s: There is strong preclinical evidence that alternate-day fasting can delay the onset and progression of the disease processes in animal models of Alzheimer’s disease and Parkinson’s disease. Intermittent fasting increases neuronal stress resistance through multiple mechanisms, including bolstering mitochondrial function and stimulating autophagy, neurotrophic-factor production, antioxidant defenses, and DNA repair.

• Fasting reduces autoimmune problems: Two recent pilot studies showed that patients with multiple sclerosis who adhere to intermittent-fasting regimens have reduced symptoms in as short a period as 2 months. Because it reduces inflammation, intermittent fasting would also be expected to be beneficial in rheumatoid arthritis, and indeed, there is evidence supporting its use in patients with arthritis.

• Fasting looks like it might reduce the harm from concussion: Intermittent fasting after injury was also effective in ameliorating cognitive deficits in a mouse model of traumatic brain injury.

These quotations speak for themselves. But I do want to comment on these two paragraphs:

Despite the evidence for the health benefits of intermittent fasting and its applicability to many diseases, there are impediments to the widespread adoption of these eating patterns in the community and by patients. First, a diet of three meals with snacks every day is so ingrained in our culture that a change in this eating pattern will rarely be contemplated by patients or doctors. The abundance of food and extensive marketing in developed nations are also major hurdles to be overcome.

Second, on switching to an intermittent-fasting regimen, many people will experience hunger, irritability, and a reduced ability to concentrate during periods of food restriction. However, these initial side effects usually disappear within 1 month, and patients should be advised of this fact.

To me, the great secret is that switching to a low insulin-index diet first (see “Forget Calorie Counting; It's the Insulin Index, Stupid”) makes fasting much easier, even at the beginning. On the sequencing I recommend, see:

• 3 Achievable Resolutions for Weight Loss

• 4 Propositions on Weight Loss

For annotated links to other posts on diet and health, see:

• Miles Kimball on Diet and Health: A Reader's Guide

For example, here is what the first section looks like:

I. The Basics

• 3 Achievable Resolutions for Weight Loss

• Stop Counting Calories; It's the Clock that Counts

• 4 Propositions on Weight Loss

• Forget Calorie Counting; It's the Insulin Index, Stupid

• Obesity Is Always and Everywhere an Insulin Phenomenon

• Maintaining Weight Loss

• Why a Low-Insulin-Index Diet Isn't Exactly a 'Lowcarb' Diet

• What Steven Gundry's Book 'The Plant Paradox' Adds to the Principles of a Low-Insulin-Index Diet

• The Problem with Processed Food

• On Exercise and Weight Loss

• David Ludwig: It Takes Time to Adapt to a Lowcarb, Highfat Diet

• Competition from Generic Insulin Would Do a Lot to Reduce Medical Costs; But Reducing the Incidence of Type II Diabetes by Changes in the American Diet Would Do Much More

• Jonathan Shaw: Could Inflammation Be the Cause of Myriad Chronic Diseases?