Valter Longo spent childhood summers in Molochio, the village in the Calabria region of southern Italy where his parents were born. It happens to have a high concentration of centenarians. Longo grew up to earn a Ph.D. in biochemistry and to study how food influences longevity. Although based in Los Angeles and Milan, he often returned to Molochio, hoping to discover the life-extending magic of the local diet. Not surprisingly, the village elders reported eating simply and sparingly: vegetables, beans, fruit, olive oil, pasta, and minimal meat.
But that wasn’t the whole story.
“When we talk to centenarians we often hear, ‘You know, we went through moments, through times, where there was just no food at all,’” he says.
As a young laboratory researcher, Longo starved yeast to tease out how nutrient deprivation affects gene expression and other biological processes associated with longer life. He became convinced that fasting can delay aging, prevent many illnesses that come along with growing older, and help more of us blow past age 100 by resetting our metabolism and cleaning out cellular debris. But few people will stick to a days-long fast, and extended fasting can cause muscle loss and other problems.
So Longo spent years developing, testing, and fine-tuning a diet that tricks our bodies into responding as if we’re eating nothing at all. It is very low in calories, sugars, and protein, and high in unsaturated fats.
In experiments with middle-aged mice, Longo showed that a fasting-mimicking diet, or FMD, as he calls it, extends lifespan, revitalizes the immune system, and lowers the incidence of cancer. The diet also improved learning and memory in older mice, delayed cognitive decline in mice bred to develop Alzheimer’s, and improved the efficacy of cancer treatment.
Longo packaged the fasting-mimicking diet into a food kit, which includes nutrient-rich crackers, olives, soup mixes, herbal tea, and supplements. A study of 71 healthy adults who followed the diet, for five consecutive days once a month for three cycles, found it reduced body fat, body weight, blood pressure, glucose, and C-reactive protein—all good things for staving off heart disease, type 2 diabetes, and other chronic ailments. The people at highest risk for these conditions improved the most.
In 2022, Longo and his colleagues reported that this diet improved the metabolic health of patients with prostate cancer, raising the possibility that the regimen could serve as a vital adjunct to conventional cancer therapies.
Now Longo is putting his diet to its biggest test. He is recruiting 500 people, ages 30 to 65, from Molochio, Varapodio, and neighboring villages for a head-to-head comparison of the effects of normal eating and FMD. He hopes the study will demonstrate, convincingly, that sending the body into fasting mode can improve the health of many adults and reverse age-related molecular and cellular damage at the root of the conditions that bedevil us late in life.
The popularity of fasting
In 2022, 10 percent of Americans surveyed by the International Food Information Council said they fasted intermittently. By contrast, 2 percent reported following a vegan diet, 3 percent said they were vegetarian, and 5 percent said they ate a Mediterranean-style diet. However, the meaning of “intermittent fasting” varies widely—12 hours a day, 16 hours, alternate days, one day a week.
Diet fads come and go with such regularity it would be easy to chalk up the current mania for intermittent fasting as a passing fancy. But in the year-plus I spent reporting on the science of longevity for National Geographic, I was impressed by the number of researchers who routinely take a time-out from food on the strength of evidence showing health benefits for the practice.
“It is really proven, and I think validated—fasting is good,” says Tzipi Strauss, a physician who is establishing a clinical center for healthy longevity at Israel’s Sheba Medical Center. “You don’t need to eat three times a day. Or every three hours. No. We are not babies. We don’t need to grow.”
Evelyne Yehudit Bischof, chief associate physician of internal medicine and oncology at Renji Hospital, Jiaotong University School of Medicine in Shanghai, eats nothing before 10 a.m. or after 4 p.m. When I received several emails she sent at midnight, I wondered how she worked so late without falling over, famished. “I eat a lot during the hours I’m allowed,” she says.
Satchidananda Panda of the Salk Institute for Biological Studies in California—an expert on circadian clocks, the internal system that regulates body rhythm—is an intermittent faster, too. According to his studies, limiting the time spent eating keeps cells and organs, the brain included, running in sync. His research tells him that ideally, he and his family would skip food for 16 hours daily. But he didn’t think he could sell his wife and daughter on fasting longer than 12 hours.
All this variation and improvisation leaves Longo determined to answer fundamental questions. “Fasting is just a word, like eating,” he says. “You have to move into exactly what kind of fasting works and why.”
Craze or cure?
Today’s fasting mania grew out of more than a century of research showing that extreme calorie restriction—a reduction of 20 percent to 40 percent—dramatically extends the lives of animals, including worms, flies, mice, rats, and rhesus monkeys, as long as they get the nutrients they need. No other antiaging intervention comes close. These studies also demonstrate that extremely low-calorie diets significantly reduce the incidence of age-related diseases, especially cancer.
Lab animals are typically fed only once or twice a day—they don’t watch Netflix and munch popcorn at all hours. For decades scientists overlooked the possibility that the hours without food might contribute to the health and longevity gains among calorie-restricted animals. Now it’s apparent than when we eat may be more important for longevity than how much.
In 2022, scientists at the University of Texas Southwestern Medical Center reported the results of an elaborate four-year experiment tracking hundreds of mice over their whole lives. Automated feeders allowed some mice to eat as much as they wanted, while sharply reducing calories for others and allowing that group access to food on different schedules—within a two-hour window, within 12 hours, around the clock, day vs. night. Calorie restriction alone increased the lifespan of the animals by 10 percent. Coupled with limiting chow time to two hours at night, peak activity time for mice, the diet extended their lifespan by 35 percent. That would translate into about 25 years, on average, for humans.
It would take decades—and thousands of volunteers with the superhuman discipline to adhere to a fasting regimen all that time—to determine whether strictly limiting when we eat can give us so much more time on Earth. But the practice has clear upsides. A 2019 study followed 2,001 heart patients and found those who routinely fasted were much more likely to be alive four years after a common procedure, cardiac catheterization, compared with patients who never fasted, did it briefly, or stopped many years earlier.
Researchers Rafael de Cabo of the National Institute on Aging and Mark P. Mattson of Johns Hopkins University School of Medicine reviewed years of clinical trials of intermittent fasting and concluded that there is enough evidence of the health benefits that physicians should be trained on the subject and offer guidance to patients.
Of course, what we eat matters, too. Researchers at the University of Bergen in Norway recently estimated that a 20-year-old who cuts out hamburgers, hot dogs, white bread, and other staples of the Western diet, and makes a habit of eating beans, lentils, whole grains, nuts, fruits, and vegetables could increase their life expectancy by up to 13 years. And as with exercise, it’s never too late to start and reap the benefits.
A 60-year-old could gain more than eight years, and an 80-year-old could add more than three years, the scientists say. They did not measure the impact of fasting on life expectancy. But Panda notes that in addition to the physiological changes induced by fasting, the discipline encourages better food choices and less snacking.
There doesn’t seem to be a downside to following a 12- to 16-hour food-free interval nightly. In 2022, Panda and his colleagues published a study of 137 San Diego firefighters, half of whom agreed to eat only within a 10-hour daily window for 12 weeks. In a region plagued by wildfires, Panda initially worried: What if 14 hours without food left a firefighter sluggish or fuzzy minded during an emergency?
“That was the most scary part for us,” he says. “If some participant is feeling weak, is not responding to a 911 call, is not getting into that fire engine within 60 seconds, that would be the end of the study.” But performance didn’t slip. Overall, the fasting group showed improvements in cholesterol and mental health, and cut back on alcohol. Those who had high blood pressure or high glucose at the start of the study saw their levels go down.
“The bottom line is, many of the fasting protocols will have some benefit that’s much better than not fasting at all,” Panda says.
How fasting works
Valter Longo directs the Longevity Institute at the University of Southern California and the Longevity and Cancer Program at the IFOM Institute of Molecular Oncology in Milan. He says his fasting-mimicking diet works in large part by activating blood stem cells, which strengthen the body’s ability to produce infection-fighting white blood cells. It happens not during the FMD cycle but when normal eating resumes. The regimen also promotes a cellular cleansing process called autophagy: Cells devour their own damaged parts, which are replaced by functional components.
In clinical trials, Longo has found that FMD switches the body from a sugar-burning mode to a fat-burning mode—essentially reprogramming metabolism, which the modern Western diet has thrown out of whack. Studies of intermittent fasting have demonstrated a similar effect, which may explain why people with metabolic risk factors such as pre-diabetes appear to benefit most.
Roughly 30 clinical trials around the world are testing FMD on people with cancer, multiple sclerosis, Alzheimer’s, kidney disease, high blood pressure, irritable bowel syndrome, “and almost any disease you can think of,” Longo says.
A kit for Longo’s five-day program is also available commercially, for close to $200. Longo says all his profits go to the Milan-based foundation that supports his research. Still, the price puts the package out of reach for many Americans, especially low-income people and people of color, who have disproportionately high rates of heart disease, cancer, and diabetes.
“It’s not scalable,” Panda says. “It’s not going to help half of the population in the U.S. who actually need this approach. They cannot afford it. They cannot even afford food, healthy food.”
I wondered why Valter Longo decided to bring a new way of eating to a region of Italy famous for centenarians and healthy traditional fare. “Nowadays, not a lot of people follow this diet,” says Romina Cervigni, scientific officer at Longo’s foundation. Roughly one-third of children and adolescents in Calabria are overweight, one of the highest rates in Italy. Sixty-one percent of residents ages 65 and older have high blood pressure, 29 percent have heart disease, and 24 percent have diabetes, with the rates shooting up as people reach their late 70s and 80s, according to the chronic disease surveillance system set up by the Italian Ministry of Health.
“We hope the study will improve life for a new generation,” says Orlando Fazzolari, the mayor of Varapodio.
Longo and his team are recruiting volunteers who are overweight and have high blood pressure, high cholesterol, high blood sugar, or other metabolic risk factors. The researchers will randomly sort people into three groups. One will eat normally, switching to the fasting-mimicking regimen for five days three times—at the start of the study, three months later, and three months after that.
The second group will follow the same FMD schedule and the rest of the time, they’ll eat what he calls “the longevity diet.” It’s nearly vegan, except for some fish, and ideally consumed within a 12-hour daily window. The final group will serve as controls, changing nothing about their diet. The study will measure changes in body mass index, numerous biological markers, and biological aging.
At the end of six months, Longo will invite the control group to switch to the longevity diet. Years of research have taught him that when people volunteer for a study and wind up getting nothing that might boost their health, they often feel cheated. The study takes place in villages with a couple thousand residents, at most, and everybody knows one another. He doesn’t want people in the control group to complain: Why did my cousin get the diet, and not I?
Calorie restriction in a pill
No antiaging intervention tested by scientists—and they’ve investigated hundreds—has had stronger, more consistent effects than calorie restriction. It boosts the lifespan of rodents by up to 50 percent. Rhesus monkeys—closer to us than mice, genetically speaking—also benefit. In one study, researchers slashed the daily calorie intake of rhesus monkeys by 30 percent for their entire adult lives, without skimping on nutrients. Those animals not only lived longer than monkeys fed standard fare, they also were less likely to develop diabetes, heart disease, cancer, and the brain shrinkage that often comes with old age.
In humans, eating the bare minimum for survival might prevent or delay some ailments, but over the long term it would cause other problems, such as bone loss. Even if the practice was safe, many of us might not think a longer life worth living if it meant walking around hungry all the time. João Pedro de Magalhães, a professor of molecular biogerontology at the University of Birmingham in England, feels that way.
“I’m terrible when I’m hungry,” he says. “I get very grumpy. So the question is, could we develop a way of getting the benefits of the health effects and longevity effects of calorie restriction without having to go on a diet? That’s something that, for decades, people have dreamed about.”
Now his lab has taken a step toward finding an answer. In a series of experiments, de Magalhães and his colleagues showed that a prescription blood pressure medication, rilmenidine, extends the lifespan of the worm C. elegans by about 20 percent—and does it by mimicking the protective biological effects of calorie restriction. The drug activates the same genetic pathways as a super low-calorie diet. It also induces what’s known as autophagy, or the clearing out of old cells, a critical process for health and one that deteriorates as we age. Worms lived longer even if they did not get the drug until they were old.
Scientists have studied other compounds that imitate the genetic and molecular action of extreme dieting. Two of the most promising drugs for slowing aging, rapamycin and metformin, act on the same pathways and mechanisms that give calorie restriction its life-extending power. But some experimental compounds that seemed promising turn out to be toxic in animals.
De Magalhães uses computational methods to find a potential calorie-restriction-mimicking pill in the vast repositories of widely used medications, ones that are already proven safe in humans. He has found that rilmenidine triggers the same protective molecular effects in mice that he saw in worms, and he plans to study whether it also increases mice lifespan.
He also hopes to investigate the anti-aging and longevity effects of the drug in people who take it for hypertension. Does rilmenidine lower their biological age? Does it reduce the risk of other age-related ailments?
It’s a long way, of course, from treating worms to treating people. When might we see a pill that safely and effectively tricks the human body into acting as if it’s on the sparsest of diets, even as we eat to our heart’s content?
“That’s the million-dollar question,” de Magalhães says. “On one hand, I’m optimistic about it. On the other hand, I’m also realistic that the benefits seen in animal models are not going to translate fully to human beings. The lifespan effects, 20 percent in worms, are going to be far more modest in humans. But if we can even only slightly increase lifespan—and it’s not just about lifespan—if we can improve the health of elderly individuals by having this prevention measure, then that would be a fantastic achievement by itself.”
This content was originally published here.
