LOS ANGELES - He knows he sounds like a snake-oil salesman.
It's not every day, after all, that a tenured professor at a prestigious university starts peddling a mail-order diet to melt away belly fat, rejuvenate worn-out cells, prevent diseases ranging from diabetes to cancer - and, for good measure, turn back the clock on aging.
But biochemist Valter Longo is convinced that science is on his side.
Longo has spent decades studying aging in yeast cells and lab mice. He now believes he's developed a diet that may boost longevity - by mimicking the effect of periodic fasting. So he's packed precise quantities of kale chips, quinoa soup, hibiscus tea, and other custom concoctions into boxes that go for $300 a pop.
Longo's ProLon diet (it stands for "pro-longevity," he says, and not "Professor Longo") reflects a growing interest in episodic fasting, which has been touted by celebrities such as Jimmy Kimmel and Benedict Cumberbatch and in best-selling books like "The Alternate-Day Diet." His approach stands out because he insists he can use certain combinations of nutrients to trick the body into thinking it's fasting without actually being on a punishing, water-only diet.
Intrigued, STAT reviewed dozens of scientific studies and talked to a half-dozen aging and nutrition experts about fasting in general and ProLon in particular. We visited Longo's lab at the University of Southern California's Longevity Institute, where slender black and white rodents pass their days in clear plastic boxes labeled "DO NOT FEED." We even tried Longo's diet for one long and rather hungry week.
Our conclusion? Fasting does appear to boost health - certainly in mice, and preliminary evidence suggests it might do so in humans as well, at least in the short term. It's not yet clear whether that's because abstaining from food prompts cellular changes that promote longevity, as some scientists believe - or because it simply puts a brake on the abundant and ceaseless stream of calories we consume to the detriment of our health. Either way, it can be a powerful force.
"We're not meant to eat three meals a day - and snacks," said Mark Mattson, a pioneer in studying the effects of intermittent fasting on the brain who runs the neuroscience lab at the National Institute on Aging.
Mice and rats on fasting regimes are slimmer, live longer, and stay smarter and physically stronger as they age. They resist tumors, inflammatory diseases, and the neurodegeneration that characterizes diseases like Parkinson's and Alzheimer's. They handily fight off infection and can even sprout new neurons. They don't end up with diabetes, autoimmune disease, high cholesterol or fatty livers.
Longo, who runs labs at both USC and at at the IFOM cancer institute in Milan, believes he knows why. Fasting, he and others argue, gives cells a break to rest, renew, rebuild themselves and, essentially, take out the trash as the body shifts from storing fat to burning it. They can't do that when the body is constantly ingesting food, stockpiling excess calories and pushing cells and organs to exhaustion.
"The animal data is very striking," Mattson said. "These aren't trivial effects on health."
Of course, many exciting findings that hold true for lab mice don't translate to more complex human biology. Small, short-term studies in humans do show that periodic fasting reduces weight, abdominal fat, cholesterol, and blood glucose, as well as proteins like C-reactive protein and IGF-1 that are linked to inflammatory diseases and cancer.
But it's not clear how long these effects last or whether they translate into any lasting clinical advantage - such as fewer heart attacks or longer lifespan.
So some experts say there just isn't enough clinical data to prove the diet does everything Longo claims. "These are only animal studies. There isn't a big body of evidence in humans," said Kristen Gradney, a dietician in Louisiana and a spokeswoman for the Academy of Nutrition and Dietetics. "It could work, but I can't confidently say that it will."
Yet even some scientists who fully understand the limitations of the data are sold.
Satchidananda Panda, a researcher at the Salk Institute for Biological Studies in La Jolla, Calif., compared mice that were allowed to eat whenever they wanted to mice that only had access to food during a 10- to 12-hour period each day. The differences were profound. The mice that fasted intermittently had no gray fur and weren't lethargic, even as they neared 2 years of age, the average mouse life span.
The results were so striking, Panda and his family have adopted the practice. He also undertakes a water-only fast for a week each year.
"Once you see these animals," Panda said, "it's hard not to follow."
Mattson, too, eats all of his roughly 1,800 calories per day in a six-hour window in the late afternoon and early evening. He hasn't eaten breakfast in 40 years.
As for Longo, he uses his own diet every few months - especially to lose weight after returning from stays in Italy. Otherwise, he often eats just two meals a day and is passionate about natural, healthy, and plant-based food.
As one of his senior researchers, Sebastian Brandhorst, put it: "Valter always gives us crap when there's junk food in the lab."
‘They thought it was crazy science'
Valter Longo was born to study aging.
Italian by birth, he spent summers in his family's ancestral home, a town called Molochio in southern Italy that's home to an unusually high percentage of centenarians. His father is 91. Exactly why the villagers live so long is a question that's always simmered in the back of Longo's head.
Now 49, Longo originally came to the U.S. to be a rock star. He enrolled at the University of North Texas, which has an acclaimed jazz guitar program. But he soured on the program when he was forced to run a marching band and turned instead to biochemistry - as a way to study aging.
He moved on to UCLA to pursue a Ph.D. with Dr. Roy Walford, who had become something of a celebrity scientist while pushing the idea that severely restricting caloric intake would extend life.
While he calls Walford a pioneer, Longo soon grew disenchanted with the extreme regimen he espoused. First, it was brutal to maintain. Then, there was what it did physically to Walford, who had been among a Biosphere 2 crew that restricted food intake dramatically during their stay in the experimental habitat. "When they exited Biosphere, they looked liked hell," Longo said. "Walford looked like a skeleton."
Walford, a colorful character known for walking across Africa and paying for med school by gaming roulette tables in Reno, Nev., had hoped to live to 120. But he died in 2004 at age 79 of ALS, a disease a number of researchers assert was exacerbated by, or even caused by, his severe diet.
At UCLA, Longo was growing frustrated with Walford's attempts to study longevity in humans, and even mice, without having adequate tools to drill down into the genetic mechanisms underlying aging. So Longo turned back to biochemistry.
He transferred to a genetics lab focused on yeast, figuring that would let him study the mechanisms of aging in the simplest of organisms.
Few people took his early results seriously. Studying aging was still considered flaky. And many scientists at the time were deeply skeptical that you could learn much about human biology by studying simple yeast.
"If someone said, 'What are you working on?' we would say oxidative chemistry," Longo said. "You couldn't say aging. That was viewed as a joke."
Convinced his work was important, Longo kept his head down and kept going. "I didn't pay attention to what people were saying," he said. In just a year, Longo was able to work out a genetic pathway to describe aging in yeast and show that food - proteins and sugars - could speed aging. It was 1994.
"I was so excited, I thought people were going to say, 'This is the discovery of the century,'" he recalled. "Of course, it was sent back - rejected."
He rewrote the paper and resubmitted. No luck. He couldn't get any of the work published without taking out every last reference to aging. The discovery he thought most important - the aging pathway - he published only in his UCLA thesis. "We would get insults from reviewers. The yeast world was the worst. They thought it was crazy science," he said.
As years passed, other groups started publishing work detailing, as Longo had, specific aging pathways, first in worms and eventually in flies. "The frustrating thing is," Longo said, "we had all of these things figured out and no one was listening."
Frank Madeo, a yeast researcher at the University of Graz in Austria, had seen Longo being dismissed at conference after academic conference. Now, he said, the work is finally being embraced. "Valter for sure is a fighter. He doesn't care what others think," Madeo said. "He did something that at first was considered weird and he was attacked. Now, it's the basis of work in so many labs."
The turning point, Longo said, came when an editor at Science recognized that his rejected paper was part of the new paradigm to understand the genetics of aging. The paper was published in 2001, seven years after he'd first submitted it. It has since been cited hundreds of times.
Once he had the aging pathway worked out, Longo went on to look more deeply at what restricting calories did to yeast cells. He found withholding food "completely reprogrammed" the yeast - cells lived longer and were resistant to threat after threat. "You could throw in any toxin you could think of and it wouldn't die," he said.
Fasting "is at the foundation of the body's ability to protect, repair, and rejuvenate itself," he said. "We started to wonder: What can we use it for?"
So he started experimenting with limiting rodents' intake of the proteins and sugars that he'd seen activate the aging pathways. (His lab cooks up a diet by hand for the animals; it's also the inspiration for the the five-day diet he sells for humans.) His team has found that the diet shows promise in restoring pancreatic cells that keep diabetes in check, boosting immune cells, and helping prevent the deterioration of myelin, which plays a role in multiple sclerosis.
San Diego computational biologist Karmel Allison, who blogs at the diabetes lifestyle site ASweetLife, took a deep dive into Longo's paper on pancreatic cells and found the data unconvincing. She thinks the improvements in mice could have simply come from their weight loss, not from any cellular change brought on by fasting.
Other scientists agree that's a key question for further study, in both mice and people. A study published in the Journal of the American Medical Association this May startled some diet researchers by showing alternative day fasting was no better at decreasing cardiovascular health risk factors than normal dieting - and was harder to maintain. (Longo maintains that the popular alternate day and 5:2 diets, where people eat up to 800 calories on their so-called fasting days, are not true fasting, just calorie reduction, and therefore don't cause the metabolic shifts and cellular improvements of his diet. He thinks at least three days of fasting are needed, though other researchers disagree.)
"In humans, is intermittent fasting only effective for weight loss because we're restricting calories? In my mind, that's the big question," said Grant Tinsley, an assistant professor of kinesiology at Texas Tech University who studies sports nutrition. "Is this just about eating fewer calories or are there unique cellular changes?"
Tinsley himself practices intermittent fasting: He restricts himself to eating during a six- to nine-hour period each day or does a 24-hour fast once a week. He likes the idea of Longo's diet. Yet he'd still like more data. "There really are no side-by-side comparisons of different fasting programs in humans," he said.
He knows firsthand, though, how hard it would be to conduct such a study. For one thing, it's hard to get corporate funding for a study involving abstaining from food. For another, human beings are prone to cheat on diets. "Obviously it's not ethical to keep people in cages for a year and feed them what you want," he said.
Longo can, however, do that with mice. And he and his lab are excited about new studies showing that fasting seems to strengthen normal cells in rodents while making cancer cells more vulnerable. Longo thinks this means fasting may increase the potency of chemotherapy while reducing its side effects.
And, indeed, small clinical trials in humans have shown patients report less fatigue and fewer gastrointestinal symptoms while fasting during chemotherapy treatments. Longo now has clinical trials underway at several cancer centers worldwide to see if his diet improves outcomes as well.
A diet that mimics fasting with beets and cider vinegar
Longo came up with the idea for the fasting mimicking diet about 10 years ago. He was trying to test the effect of a water-only diet for cancer patients. But most patients refused to fast and oncologists were worried about their already thin patients participating.
So Longo decided to devise a diet with minimal calories that would provide the nutrition the patients needed, but also confer the benefits of fasting. His lab worked out the precise amounts and types of calories, carbohydrates, proteins, and fats by testing various diets on mice.
The cancer fasting diet amounts to just 200 to 500 calories a day for four days. The ProLon diet allows 1,100 calories the first day and 800 for the next four. (Longo recommends doing the diet under a doctor's supervision and notes that it's not appropriate for people with certain health conditions, such as diabetes.)
His diet is low in protein and fat; he gets furious when he sees doctors advocating the opposite, a trendy practice he believes speeds aging.
He gets really fired up when nutritionists call fasting a fad. "Fasting is as old as it gets," he said, noting that our hunter-gatherer ancestors likely went long stretches between meals. "If 70 percent of America is obese or overweight, you would think they'd have figured out their [more traditional] interventions don't work."
To devise fasting diets that people would actually want to eat, Longo turned to Ambra Ditonno, a longtime friend who runs a popular Italian cafe in Hollywood.
The two worked together after hours in Ditonno's panini shop concocting extremely low-calorie soups - some just 30 to 45 calories per serving - out of pumpkin, beets, tomatoes, and broth. "He said, ‘I need to have something that's going to have almost no calories but still have taste.' It was really hard," Ditonno said.
It's not typical work for a scientist, but was typical for the hands-on Longo, who's not married, has no children, and is used to working long hours (though he's prone to pulling out his guitar when asked, and also does a lot of bike riding).
"He doesn't have any other interests. He's married to his job," Ditonno said. And, she added, he had a natural flair for the work: "He's Italian, so he has some idea of cooking."
They'd then freeze individual portions of the soups for delivery to cancer patients. (The soups are now manufactured in a facility and freeze-dried so they can be easily shipped and stored.) The diets include additional ingredients - algal oil supplements, specific proteins, trendy additions like flax seed, inulin, glycerol, and cider vinegar - that Longo believes act to improve health or trick the body into thinking it is fasting.
After cooking so many fasting soups, Ditonno tried the diet herself last year. She lost weight, got rid of the extra tummy fat she'd carried since having a child and eased several digestive issues. The benefits have persisted long after that initial fasting period. Like many who work with Longo and have tried the diet, she's become a convert. "I believe in it like 1,000 percent," Ditonno said.
The idea of a professor marketing his own longevity diet has raised eyebrows. "It's a tricky spot to be in," said Allison Dostal, a registered dietitian and Ph.D. from the University of Minnesota. She was part of a watchdog team that wrote a scathing review of a press release touting one of Longo's studies that was put out by USC, which also stands to profit if the diet is a financial success. "It's not something I've generally seen."
The cost of ProLon has also raised questions, especially since there's no proof this particular combination of foods works better than any other ultra-low-calorie diet or episodic fast.
"The diet's OK," Mattson said. "I'm just thinking about the people who can't afford it. A lot of obese people are of low socioeconomic status. That's the target population that could really benefit most."
Longo created a company, L-Nutra, to market the diet, and retains majority ownership. He intends to funnel any personal profits into a nonprofit to fund research. For now, not much money is rolling in, though he says about 5,000 people have used ProLon - some paying customers, some research subjects. He hopes to one day receive FDA approval to market the diet as a tool to help prevent diabetes, but that's well in the future.
Panda, the Salk Institute researcher, calls Longo's approach a smart business move.
"The general public wants something encapsulated, they want a prescription," he said. "Valter's done a very smart thing. He's encapsulated fasting."
Correction: A previous version of this story misstated the location of the University of Graz and Allison Dostal's academic affiliation.