A human has about 16 billion cortical neurons, and in the tip of a woman’s clitoris alone are 8,000 neurons—a man’s penis has a pitiable 4,000. More than 100 million neurons (nerve cells) are in our stomach, and more than 500 million pack the enteric nervous system, which is sometimes called the “brain in the gut.” This number is slightly fewer than the neurons in a dog’s cerebral cortex. The stomach’s cells and nerves translate what we eat or don’t eat into neural signals that become the sensations that help define our existence. If the cries of the digestive network go unanswered, an amazing internal concatenation of biochemical machinery activates.

At the start of a fast, the stomach commands production of certain hormones, or signaling molecules. Among these are ghrelin, which stimulates hunger and lowers the level of the hormone leptin, which produces a feeling of fullness. Leptin is secreted by fat tissue in proportion to its mass, so the more fat, the more leptin. These hormones trundle along, taking up to ten minutes before their impact is felt. Ghrelin activates nerve cells within the hypothalamus—a part of the forebrain—and produces two proteins that cause hunger, neuropeptide Y and agouti-related peptide (engagingly associated with a large South American rodent, the agouti, because of the role that the peptide’s molecular cousin—agouti-signaling protein—plays in coloring the bristles of the beast).

These peptides are complemented by a recently discovered lightning-fast signaling node in the digestive system, a neural circuit that sends messages to the brain within milliseconds. The node operates via synaptic transmission: certain cells lining the stomach emit glutamate, a neurotransmitter that affects the vagus nerve, a neural highway between the brain, gut, hearts, and lungs. The body uses the same neurotransmitter in neuronal synapses from cells of the inner ear and retina. Researchers think the electrical signals provide the brain with “precise spatial and temporal information about gut contents.”

If the cries of the digestive network go unanswered, an amazing internal concatenation of biochemical machinery activates.

Hormonal manipulations and electrical signaling engender more hunger pangs and growling, clear signals that all is not right with the world, just in case our consciousness has not already registered the fact that we are not plying ourselves with the usual amount of food. The primal self urges us to reach for a “friendly bite,” a gentle reassurance that we’re in familiar territory—safe, warm, and with a food supply readily at hand. At this point in the fast, to suppress such natural inclinations requires conscious redirection.

For the mind to betray instinct is a rebellion of the most basic sort. The body is firmly on the side of instinct. The spirit is leading an insurrection, and the body responds by calling for a return to unthinking habit. This self-induced (mild) torture lasts anywhere from forty-eight to seventy-two hours, at which point the call for outside assistance diminishes, the body gives up the fight, and resorts to internal resources.

Certain foods provide carbohydrates (fibers, starches, and sugars), which are broken down via the digestive process into glucose, which provides most of the body’s energy. As the fast proceeds, the body recalibrates, in effect going into lockdown mode. Our corporal machine continues along an alternate pathway, working toward a transformed self via gluconeogenesis (the process by which glucose forms) and adaptive thermogenesis (the process by which the body heats itself).

It does so first by using up most of the excess glucose stored in the muscles and liver as glycogen, which can easily be processed into energy. There is a lowish reserve of glycogen to begin with, typically only enough to provide energy for a hard-driving athlete to perform for an hour or so. (A fasting person at rest has about sixteen hours’ worth of glycogen to draw on.) As blood sugar levels drop, that underappreciated organ (at least for those of us without diabetes), the pancreas, joins the fray by producing glucagon, a hormone that acts on the liver, stimulating the production of glycogen and reducing consumption of glucose by the liver, all so the bloodstream can maintain a steady level of glucose. The priority is to keep the brain constantly supplied with calories in the form of glucose.

About three or four days into a fast, when glycogen reserves run very low, the body turns to fatty acids (adipose tissue triglyceride) derived from fat (adipose tissue) stored throughout the body. The brain can only use highly refined fatty acids, so low levels of insulin signal the liver to switch its production focus to metabolizing ketone bodies from fatty acids. Ketones are an emergency fuel that allow the body to go relatively long periods without food.

A reliable indicator of ketosis—highly elevated levels of ketone bodies—is the smell of acetone on a faster’s breath and a distinct taste that has been variously described as lemon drops or walnuts: as the liver metabolizes fatty acids, it produces three types of ketones, one of which is acetone, the same stuff found in nail polish remover. Thanks to acetone’s high vapor pressure (meaning that it is volatile, and evaporates more quickly), it can cross the membrane barrier into the lungs. The result is breath that smells of fruit or alcohol. Breath acetone concentration has been shown to be an effective way to measure fat loss; the more acetone, the higher the rate of fat loss.

As its beneficial effects have become known, an avalanche of studies and popular books extolling the virtues of induced ketosis has resulted. Since the 1920s, nutritional ketosis (where caloric intake equals energy expenditure) has been used as a treatment for epilepsy because ketones provide elevated energy to the brain, which causes a reduction in seizures.

In 2008, the largely anecdotal evidence for the effectiveness of fasting as a treatment for epilepsy was backed up by a five-year study involving 145 children aged two to sixteen in England. All the children chosen for the study were suffering from a minimum of seven epileptic attacks a week. After going on a ketogenic diet for three months, 38 percent showed a decrease in seizures, while in the control group (those receiving medications as usual), 37 percent showed an increase in seizures. Seven percent of those on the ketogenic diet reported a drop in seizures of 90 percent or more, versus zero percent in the control group.

The spirit is leading an insurrection, and the body responds by calling for a return to unthinking habit.

While the chorus is far from unanimous—some studies show that ketone bodies, because they are more potent than glucose, may adversely affect blood flow, leading to vascular damage and/or high cholesterol (hypercholesterolemia)—arguments for the health benefits of fasting accumulate on practically a daily basis, reinforcing the idea that it can be a powerful refresher for the body and help heal ailing cells. “Ketone bodies are not just fuel used during periods of fasting,” wrote Rafael de Cabo, chief of the Translational Gerontology Branch at the U.S. government’s National Institute on Aging, and Mark Mattson, professor of neuroscience at Johns Hopkins and former chief of the neurosciences laboratory at the National Institute on Aging, in the New England Journal of Medicine. “They are potent signaling molecules with major effects on cell and organ functions.” Thanks in large part to these high-energy miracle compounds, metabolic switching induced by fasting prompts repair and renewal down to the molecular level.

As part of a study of fasting’s effects on aging, de Cabo and Mattson found fasting benefits for those suffering from obesity and diabetes mellitus, cancer, cardiovascular disease, neurodegenerative disorders, postoperative recovery, and even (on the basis of animal models) for people preparing to undergo surgery: “Intermittent-fasting regimens reduce tissue damage and improve functional outcomes of traumatic and ischemic tissue injury [resulting from poor blood circulation]….Preoperative fasting reduces tissue damage and inflammation and improves the outcomes of surgical procedures.”

In the course of their consideration of fasting, de Cabo and Mattson pointed to the Okinawa Centenarian Study, a Japanese Ministry of Health-funded program to determine why such a remarkable number of Ryukyu Islanders live very long lives (Okinawa is the largest of the islands). Okinawans living a traditional lifestyle incorporated what is essentially a permanent fasting regime—a low-calorie diet from energy-poor but nutrient-rich sources (lots of green leafy and yellow root vegetables, small amounts of fish and meat). They had a mortality rate that was strikingly skewed compared to the rest of Japan.

The three gerontologists who headed the research noted that “death rates from heart disease, cancer and cerebral vascular disease were found to be only 60 to 70% of that of the Japan average and the all-cause mortality rate for 60- to 64-year-olds was only half that of other Japanese….Thus, life expectancy at older ages is extremely long in Okinawa. For the septuagenarian cohort, life expectancy from age 65 is the longest in Japan, and possibly the world, at 24.1 years for females and 18.5 years for males.” There are four to five times the number of centenarians in Okinawa as in most industrialized countries.

The trick is calorie restriction, even to the degree of eating on an energy deficit—Okinawan septuagenarians in the study ate “approximately 11% fewer calories (approximately 1,785 kcal per day) than would normally be recommended for maintenance of body weight.” If growing old is the goal, long-term calorie restriction, which results in delayed aging in studied populations, seems a necessary component of the plan. As the population ages rapidly in industrialized countries—a fifth of the American population is expected to be over the age of sixty-five by the year 2040, more than double that in 2000; it was barely 4 percent in 1900—fasting in the form of caloric restriction is certain to become a topic of greater relevance.

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From The Fast: The History, Science, Philosophy, and Promise of Doing Without by John Oakes. Copyright © 2024. Available from Avid Reader Press, an imprint of Simon & Schuster.