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Professor Valter Longo

The findings point to the potential of using a fasting-mimicking diet as “medicine,” according to the researchers. A fasting-mimicking diet, or FMD, is a low-calorie diet that “tricks” the body into a fasting state. 

One group of mice ate a high-calorie, high-fat diet (with 60% of their calories from fat) and became unhealthy and overweight. A second group of mice ate the same poor diet as the first one for approximately 4 weeks, followed by five days where they were fed an FMD and two days of a normal, healthy diet.   

Study authors say those brief diet interventions were sufficient for that second group to return to normal levels of cholesterol, blood pressure and weight. Notably, the mice who ate the fasting-mimicking diet for five days out of each month lived as long as a third group of mice that was consistently fed a healthy diet.  

In humans, obesity caused by a high-fat, high calorie diet is a major risk factor for metabolic syndrome, diabetes and cardiovascular disease.  

“The study indicates that it’s possible for mice to eat a relatively bad diet that is counterbalanced by five days of a fasting-mimicking diet,” said study senior author Valter Longo, the director of the Longevity Institute at the USC Leonard Davis School of Gerontology and professor of biological sciences at the USC Dornsife College of Letters, Arts and Sciences. “Our major discovery is that intervening with this diet made their hearts more resilient and better functioning than the mice who only ate a high-fat, high-calorie diet.”  

The study authors say cycles of FMD appeared to prevent obesity in mice by reducing the accumulation of visceral and subcutaneous fat — all without causing lean body mass loss. FMD cycles also appeared to improve heart function and prevent high blood sugar and high cholesterol.   

According to researchers, the effect of FMD cycles on gene expression indicated a role for fat cell reprogramming in obesity prevention. Specifically, the diet’s impact on fat accumulation and cardiac aging could explain protection from early death caused by a high-fat, high-calorie diet.  

The researchers caution these results should not be misinterpreted. They emphasize that they don’t recommend that humans should eat a high-calorie, high-fat diet that’s mitigated by periodic fasting.   

They say, however, the potential benefits of counteracting poor diets in this way should be further studied in clinical trials. These strategies could provide potential health benefits for people who may not be willing or able to change their diets on an everyday basis.   

 The most effective diets at preventing or mitigating obesity in humans, including the ketogenic diet, require often radical and daily changes in dietary habits, the study authors say. Those requirements result in very low long-term compliance.  

Longo said the study may indicate a “sweet spot” for the FMD in mice of five days a month.   

“Even after the mice in experimental group went back to their high-fat, high-calorie diet, the improved fat breakdown in their bodies continued for a fairly long period,” Longo explained. “Is there a similar sweet spot for humans, where you can intervene for a few days and still keep breaking down fat for several weeks?   

Early FMD trials indicate potential health benefits for humans, he added. Several clinical studies published by Longo and colleagues indicate that a monthly FMD caused loss of fat mass without loss of muscle mass and improved cardiometabolic risk factors, especially in overweight or obese humans. They say this new mouse study shows that these monthly FMD cycles can actually restore normal heart and metabolic health and lifespan in animals fed a high-fat and high-calorie diet, a lifelong study that cannot be done in humans. 

More about the study  

Additional authors include Amrendra Mishra, Hamed Mirzaei, Novella Guidi, Gerardo Navarrete, Min Wei, Sebastian Brandhorst, Stefano Di Biase and Todd E. Morgan of the Longevity Institute and the USC Leonard Davis School of Gerontology; Manlio Vinciguerra of the International Clinical Research Center, St Anne’s University Hospital, Brno, Czech Republic; Alice Mouton of the Department of Ecology and Evolutionary Biology at UCLA; Marina Linardic and Matteo Pellegrini of the Department of Molecular, Cell and Developmental Biology at UCLA; Francesca Rappa and Rosario Barone of the Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo; S. Ram Kumar of the Department of Surgery at the Keck School of Medicine of USC; Peter S. Conti of the Molecular Imaging Center, Department of Radiology at the Keck School of Medicine at USC; Michel Bernier and Rafael de Cabo of the Translational Gerontology Branch, Intramural Research Program of the National Institute on Aging at the National Institutes of Health.  

Funding for the study was provided by the USC Edna Jones Chair fund and National Institutes of Health grant P01 AG055369-01 to Longo. The work was also funded in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. The researchers also acknowledge support from the USC Molecular Imaging Center and USC Leonard Davis School Aging Murine Phenotyping Core Facility. Mouton was supported by UCLA QCB Collaboratory Postdoctoral Fellowship. Computational and storage services associated with the Hoffman2 Shared Cluster were provided by the UCLA Institute for Digital Research and Education’s Research Technology Group.  

Longo is the founder of and has an ownership interest in L-Nutra; the company’s food products are used in studies of the fasting-mimicking diet. Longo’s interest in L-Nutra was disclosed and managed per USC’s conflicts-of-interest policies. USC has an ownership interest in L-Nutra and the potential to receive royalty payments from L-Nutra. USC’s financial interest in the company has been disclosed and managed under USC’s institutional conflict of interest policies.  

Top: illustration by Jonathan Haase

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“It was astonishing and sad in so many ways,” she said.

From that moment on, she resolved to become part of the solution in helping people live more healthfully.

Amos, who holds a bachelor’s degree in theater, decided to go back to college to beef up the science side of her CV. She had every intention of earning that degree from her alma mater.

But when she learned about USC’s innovative Master of Science in Nutrition, Healthspan and Longevity (MSNHL) program, she knew it could support her in achieving her goals. Offered both online and on-campus, the MSNHL is a product of USC’s top-ranked Leonard Davis School of Gerontology. The degree prepares graduates for a wide range of careers that all have one aim: helping people achieve the healthiest life possible as they age.

Amos joined the MSNHL’s first cohort after a symposium where she heard its director, Associate Clinical Professor Cary Kreutzer, EdD, MPH, RDN, FAND, discuss the program’s offerings — and renowned faculty.

“She said one of the professors would be Valter Longo, whose studies I had read in my prerequisite courses,” Amos recalled. “To me, the thought that I would be learning directly from the researchers conducting groundbreaking work seemed too good to be true.”

The degree program, Amos added, “lived up to every expectation.”

Using Nutrition to Fight Alzheimer’s

Longo, who directs the USC Longevity Institute and serves as the Edna M. Jones Chair in Gerontology, is an expert in researching how nutrition might stave off Alzheimer’s and other age-related diseases. Amos found that focus of special — and personal — interest.

“My family has a history of Alzheimer’s,” she said, and her grandmother died of the disease. As such, Amos wanted to learn all she could to help protect others from its ravages.

She also knew she wanted to take the entrepreneurial path in sharing dietary interventions that could potentially slow or even reverse neurodegenerative decline.

Although the MSNHL program is already noted for the success of its graduates in jobs ranging from hospital-based nutrition therapy to corporate and sports wellness, Amos said, “I wanted to go into private practice right off the bat.”

Launching the Amos Institute

The program provided Amos with all the grounding needed to pass the national test for becoming a registered dietitian nutritionist. She also became certified by the Institute for Functional Medicine. Amos regards functional medicine, which uses a holistic approach to addressing the root causes of disease, as “the wave of the future.”

Armed with this knowledge, she launched the Amos Institute to offer practical strategies for strengthening the brain and body.

“It’s a virtual platform with a cognitive health program consisting of 26 video lessons,” she explained.

The institute’s dynamic website also features recipes and a blog with updated, health-related information. Clients can even sign up for one-on-one counseling sessions with Amos or her staff of dietitians.

“Some people need more individualized attention, like having their lab work analyzed or customized meal plans created,” Amos said.

The USC Leonard Davis program and the Amos Institute both address epigenetics — the environmental and behavioral factors that interact with our genes to either worsen or ease the risk of Alzheimer’s and other conditions associated with aging.

“I learned a lot about that from my time at the school, and I’ve been able to build on this knowledge since,” she said.

Whether studied remotely or in-person, the MSNHL program fosters real-world expertise.

“Clinical experiences are a requirement,” Amos noted.

To fulfill it, she performed an internship at the USC Norris Comprehensive Cancer Center.

“That was another wonderful opportunity because of my interest in chronic illness,” she said.

Then, at what she called “the other end of the spectrum,” Amos conducted rotations in USC residential dining halls. She also assisted in providing nutritional counseling at USC’s Engemann Student Health Center.

Although Amos was able to intern within USC, students pursuing the MSNHL degree can take advantage of internships wherever they live. Remote students also complete a capstone project that is presented at a dietetics conference or published in a peer-reviewed journal.

“One of the wonderful things about the program is the flexibility it offers,” Amos said.

A Mediterranean Diet for Healthy Aging

Amos also traveled with fellow USC Leonard Davis Gerontology students to study in Italy, which was the highlight of her time in the program.

“We were learning from Longo, but he also brought in tons of guest lecturers,” she recalled.

The month-long program also enabled students to engage in observational learning.

“Being able to study fasting, fasting mimicking [a reduced-calorie regimen that fools the body into thinking it’s going without food] and epigenetics in the context of the Mediterranean diet — while being in the Mediterranean — was incredible,” Amos said.

Continuing the Journey

After earning her theater degree, Amos lived in London while deciding whether her future lay in the stage. Ultimately, she journeyed from the performing arts to the sciences to help prevent Alzheimer’s through nutritional interventions.

But the essence of performing is empathic communication, and, through the Amos Institute, she connects with clients from some 13 countries around the world.

“Our focus is to help people optimize their brain health — and by doing so, increase their health span with a comprehensive, accessible and affordable program,” Amos explained.

While Alzheimer’s will remain a specialization, she hopes to develop strategies for helping to alleviate the damage caused by other chronic diseases. She is also working to train future RDs as a guest lecturer at USC, providing many MSNHL students with real-world insights and guidance.

As her journey of assisting others continues, Amos said, “I wouldn’t change anything about the path that I’ve taken. There are lots of ups and downs with opening your own practice, but I’ve learned a lot along the way.”

The information on this website is not intended as a substitute for medical advice, and individuals should consult with their doctor or dietitian before making changes to their diets.

Learn more about the online Master of Science in Nutrition, Healthspan and Longevity program today.

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Professor Valter Longo

A USC-led team of scientists has found that a fasting-mimicking diet combined with hormone therapy has the potential to help treat breast cancer, according to newly published animal studies and small clinical trials in humans.

In studies on mice and in two small breast cancer clinical trials, researchers at USC and the IFOM Cancer Institute in Milan — in collaboration with the University of Genova — found that the fasting-mimicking diet reduces blood insulin, insulin-like growth factor 1 (IGF1) and leptin. In mice, these effects appear to increase the power of the cancer hormone drugs tamoxifen and fulvestrant and delay any resistance to them. The results from 36 women treated with the hormone therapy and fasting-mimicking diet are promising, but researchers say it is still too early to determine whether the effects will be confirmed in large-scale clinical trials.

The research was published in the journal Nature.

“Our new study suggests that a fasting-mimicking diet together with endocrine therapy for breast cancer has the potential to not only shrink tumors but also reverse resistant tumors in mice,” said Valter Longo, the study’s co-senior author and the director of the Longevity Institute at the USC Leonard Davis School of Gerontology and professor of biological sciences at the USC Dornsife College of Letters, Arts and Sciences. “We have data that for the first time suggests that a fasting-mimicking diet works by changing at least three different factors: IGF1, leptin and insulin.”

The researchers say the two small clinical trials are feasibility studies that showed promising results, but they are in no way conclusive. They believe the results support further clinical studies of a fasting-mimicking diet used in combination with endocrine therapy in hormone-receptor-positive breast cancer.

The scientists also contributed to a recent clinical study of 129 breast cancer patients conducted with the University of Leiden. The results, published last month in Nature Communications, appeared to show increased efficacy of chemotherapy in patients receiving a combination of chemotherapy and a fasting-mimicking diet.

Promising results, but additional studies are needed

In the two new small clinical trials — one of which was directed by the study co-corresponding author Alessio Nencioni — patients with hormone-receptor-positive breast cancer receiving estrogen therapy along with cycles of a fasting-mimicking diet seemed to experience metabolic changes similar to those observed in mice. These changes included a reduction in insulin, leptin and IGF1 levels, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity, so further studies in humans is needed.

“Some patients followed monthly cycles of the fasting-mimicking diet for almost two years without any problems, suggesting that it is a well-tolerated intervention,” Nencioni said. “We hope this means that this nutritional program that mimics fasting could one day represent a weapon to better fight cancer in patients receiving hormone therapy without serious side effects.”

“The results in mice are very promising. And the early clinical results show potential as well, but now we need to see it work in a 300- to 400-patient trial,” Longo explained.

The data also suggest that in mice, the fasting-mimicking diet appears to prevent tamoxifen-induced endometrial hyperplasia, a condition in which the endometrium (or the lining of the uterus) becomes abnormally thick. The study authors believe this potential use of the fasting diet should be explored further, given the prevalence of this side effect of tamoxifen and the limited options for preventing it.

Approximately 80% of all breast cancers express estrogen and/or progesterone receptors. The most common forms of hormone therapy for these breast cancers work by blocking hormones from attaching to receptors on cancer cells or by decreasing the body’s hormone production. Endocrine therapy is frequently effective in these hormone-receptor-positive tumors, but the long-term benefits are often hindered by treatment resistance.

Fasting as a “nontoxic wildcard”

Several clinical trials, including one at USC on breast cancer and prostate patients, are now investigating the effects of the fasting-mimicking diets in combination with different cancer-fighting drugs.

“I like to call it the nontoxic wildcard for cancer treatment,” Longo said. “These clinical studies we have just published — together with the many animal studies published in the past 12 years — suggest that cycles of the fasting-mimicking diet has the potential to  make standard therapy more effective against different cancers, each time by changing a different factor or nutrient important for cancer cell survival.”

Additional authors include Irene Caffa, Francesca Valdemarin, Pamela Becherini, Lorenzo Ferrando, Francesco Piacente, Michele Cilli, Luca Mastracci, Anna Laura Cremonini, Raffaella Gradaschi, Carolina Mantero, Alberto Ballestrero, Gabriele Zoppoli, Michele Cea, Patrizio Odetti, Fiammetta Monacelli and Samir G. Sukkar of IRCCS Ospedale Policlinico San Martino, Genoa, Italy;  Vanessa Spagnolo, Valerio G. Vellone, Giulia Salvadori and Filippo De Braud of the Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy; Claudio Vernieri and Salvatore Cortellino of IFOM, FIRC Institute of Molecular Oncology, Milan, Italy; Annalisa Arrighi of the Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy; Min Wei and Sebastian Brandhorst of USC Longevity Institute; Chiara Zucal, Silvano Piazza and Alessandro Provenzani of the Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, Trento, Italy; Else Driehuis and Hans Clevers of Oncode Institute and Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands;  Alberto Tagliafico of the Department of Health Sciences, University of Genoa, Genoa, Italy; Mario Passalacqua of the Department of Experimental Medicine, University of Genoa, Genoa, Italy.

The study was supported in part by the Associazione Italiana per la Ricerca sul Cancro (AIRC; IG#17736 and #22098 to A.N.; IG#17605 to V.D.L.; IG#21548 to A.P.; and MFAG#22977 to C.V.), the Fondazione Umberto Veronesi (to A.N.), the Italian Ministry of Health (GR-2011-02347192 to A.N.), the 5 × 1000 2014 Funds to the IRCCS Ospedale Policlinico San Martino (to A.N.), the BC161452 and BC161452P1 grants of the Breast Cancer Research Program (U.S. Department of Defense; to V.D.L. and to A.N., respectively), the U.S. National Institute on Aging-National Institutes of Health (NIA–NIH) grants AG034906 and AG20642 (to V.D.L.), and the Associazione Italiana contro le Leucemie-linfomi e Mieloma (AIL), Sezione Liguria.

Longo is the founder of and has an ownership interest in L-Nutra; the company’s food products are used in studies of the fasting-mimicking diet. Longo’s interest in L-Nutra was disclosed and managed per USC’s conflicts-of-interest policies. USC has an ownership interest in L-Nutra and the potential to receive royalty payments from L-Nutra. USC’s financial interest in the company has been disclosed and managed under USC’s institutional conflict of interest policies.

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Professor Valter Longo

Scientists from USC and the IFOM Cancer Institute in Milan have found that a fasting-mimicking diet could be more effective at treating some types of cancer when combined with vitamin C.

In multiple studies on mice, researchers found that the combination delayed tumor progression in multiple mouse models of colorectal cancer; in some mice, it caused disease regression. The results were published in the journal Nature Communications.

“For the first time, we have demonstrated how a completely nontoxic intervention can effectively treat an aggressive cancer,” said Valter Longo, the study’s senior author and the director of the USC Longevity Institute at the USC Leonard Davis School of Gerontology and a professor of biological sciences at the USC Dornsife College of Letters, Arts and Sciences. “We have taken two treatments that are studied extensively as interventions to delay aging — a fasting-mimicking diet and vitamin C — and combined them as a powerful treatment for cancer.”

The researchers said that, while fasting remains a challenging option for cancer patients, a safer, more feasible option is a low-calorie, plant-based diet that causes cells to respond as if the body were fasting. Their findings suggest that a low-toxicity treatment of fasting-mimicking diet plus vitamin C has the potential to replace more toxic treatments.

Results of prior research on the cancer-fighting potential of vitamin C have been mixed. Recent studies, though, are beginning to show some efficacy, especially in combination with chemotherapy. In this new study, the research team wanted to find out whether a fasting-mimicking diet could enhance the high-dose vitamin C tumor-fighting action by creating an environment that would be unsustainable for cancer cells but still safe for normal cells.

“Our first in vitro experiment showed remarkable effects,” Longo said. “When used alone, fasting-mimicking diet or vitamin C alone reduced cancer cell growth and caused a minor increase in cancer cell death. But when used together, they had a dramatic effect, killing almost all cancerous cells.”

Longo and his colleagues detected this strong effect only in cancer cells that had a mutation regarded as one of the most challenging targets in cancer research. These mutations in the KRAS gene signal that the body is resisting most cancer-fighting treatments, and they reduce a patient’s survival rate. KRAS mutations occur in approximately a quarter of all human cancers and are estimated to occur in up to half of all colorectal cancers.

Why fasting and vitamin C work well in tandem

The study also provided clues about why previous studies of vitamin C as a potential anticancer therapy showed limited efficacy. By itself, a vitamin C treatment appears to trigger the KRAS-mutated cells to protect cancer cells by increasing levels of ferritin, a protein that binds iron. But by reducing levels of ferritin, the scientists managed to increase vitamin C’s toxicity for the cancer cells. Amid this finding, the scientists also discovered that colorectal cancer patients with high levels of the iron-binding protein have a lower chance of survival.

“In this study, we observed how fasting-mimicking diet cycles are able to increase the effect of pharmacological doses of vitamin C against KRAS-mutated cancers,” said Maira Di Tano, a study co-author at the IFOM, FIRC Institute of Molecular Oncology in Milan. “This occurs through the regulation of the levels of iron and of the molecular mechanisms involved in oxidative stress. The results particularly pointed to a gene that regulates iron levels: heme-oxygenase-1.”

The research team’s prior studies showed that fasting and a fasting-mimicking diet slow cancer’s progression and make chemotherapy more effective in tumor cells while protecting normal cells from chemotherapy-associated side effects. The combination enhances the immune system’s anti-tumor response in breast cancer and melanoma mouse models.

The scientists believe cancer will eventually be treated with low-toxicity drugs in a manner similar to how antibiotics are used to treat infections that kill particular bacteria but can be replaced by other drugs if they prove ineffective.

To move toward that goal, they needed to first test two hypotheses: that their nontoxic combination interventions would work in mice, and that results would look promising for human clinical trials. In this new study, they said they’ve demonstrated both.

At least five clinical trials — including one at USC on breast cancer and prostate patients — are now investigating the effects of fasting-mimicking diets in combination with different cancer-fighting drugs.

Additional authors include Franca Raucci and Claudio Vernieri of IFOM, FIRC Institute of Molecular Oncology, Milan; Irene Caffa and Alessio Nencioni of the Department of Internal Medicine, University of Genoa and IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Roberta Buono, Maura Fanti and Sebastian Brandhorst of the Longevity Institute, USC Leonard Davis School of Gerontology and Department of Biological Sciences; Giuseppe Curigliano of the University of Milan, Department of Oncology and Hemato-Oncology and Division of Early Drug Development, European Institute of Oncology, IRCCS, Milan; Filippo De Braud of the University of Milan, Department of Oncology and Hemato-Oncology, and Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan.

The study was funded by Associazione Italiana Ricerca sul Cancro grant number 21820 and by NIA/NIH Grant # PO1 AG055369.

Longo is the founder of and has an ownership interest in L-Nutra; the company’s food products are used in studies of the fasting-mimicking diet. Longo’s interest in L-Nutra was disclosed and managed per USC’s conflicts-of-interest policies. USC has an ownership interest in L-Nutra and the potential to receive royalty payments from L-Nutra. USC’s financial interest in the company has been disclosed and managed under USC’s institutional conflict of interest policies.

*Headline updated on June 8, 2020; story originally titled “Fasting plus vitamin C proves effective for hard-to-treat cancers.”

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Professor Valter Longo

Professor Valter Longo, director of the USC Longevity Institute, is investigating how fasting and diets that mimic fasting’s effects can help immune function, including vaccine efficacy and the body’s response to infection by viruses such as influenza and eventually COVID-19.

Fasting and fasting mimicking diets appear to “get rid of damaged or mis­guided cells and replace them with younger and more effective immune cells,” he says, improving many signs of health in mice.

The Longo laboratory is demonstrating that cycles of fasting or fasting-mimick­ing diets, followed by refeeding a normal diet, promote stem cell-dependent rejuvenation of the immune system in old mice. Early clinical trials show this process of “cleaning up” older white blood cells during short periods of fasting, then spurring the restoration of the normal levels of the infection-fighting cells when fasting stops, may also happen in humans, providing potential health benefits.

Longo says these findings support clinical trials to deter­mine whether they are effective in improv­ing immune system function in elderly humans without causing detrimental side effects and increasing vaccination efficacy in older adults. Upcoming trials will test the fasting-mimicking diet’s effect on flu, and, if funded and when it becomes available, coronavirus vaccination in humans, he adds.

Vaccine efficacy is an especially important issue for older adults due to immunosenescence – the gradual decline of immune system function with age – and the higher risk of serious complications  from viral infection. On average, the seasonal flu vaccine has a response rate of slightly above 50 percent, meaning almost half of older vaccine recipients don’t make enough antibodies to successfully fight the virus.

Some early findings also indicate that fasting could provide mice with more resistance to viral infection itself. “We want to see if certain dietary interventions that can make a virus less infectious or cause fewer negative effects,” Longo says.

Earlier trials of the fasting-mimicking diet reduced cardiovascular disease risk factors, including blood pressure and signs of inflammation (measured by C-reactive protein levels), as well as fasting glucose and reduced levels of IGF-1, a hormone that affects metabolism. It also shrank waistlines and resulted in weight loss, both in total body fat and trunk fat, but not in muscle mass. In cancer patients, the fasting-mimicking diet appeared to sensitize cancer cells to chemotherapy and lessen treatment side effects.

Trial participants on the special diet were required to eat food products supplied by the nutrition company L-Nutra during fasting periods of just five days each month. The diet, which was designed to mimic the results of a water-only fast, allowed for participants to consume between 750 and 1,100 calories per day. The meals for the fast-mimicking diet contained precise proportions of proteins, fats and carbohydrates.

While many of the results are promising, Longo cautions that any kind of fasting or fasting-mimicking diet should only be undertaken with a doctor’s guidance in those that have diagnosed diseases or suspect having a disease. Sheltering in place during the COVID-19 pandemic may provide an opportunity for individuals to try a fast or fasting-mimicking diet especially those who are overweight or are gaining weight, but he advises that the most important thing to do in the face of potential illness is to stay well-nourished in general, especially for the essential workers who are at the highest risk for exposure.

Longo encourages a balanced pescatarian or Mediterranean diet versus long-term restrictive, low-calorie dieting. The immune system can get depressed with a poor diet or a diet that is too restrictive, he says. “This is not the time to push yourself to the limit.”

__

Longo is the founder of and has an ownership interest in L-Nutra; the company’s food products are used in the human studies of the fasting-mimicking diet. Longo’s interest in L-Nutra was disclosed and managed per USC’s conflicts-of-interest policies. USC has an ownership interest in L-Nutra and the potential to receive royalty payments from L-Nutra. USC’s financial interest in the company has been disclosed and managed under USC’s institutional conflict of interest policies.

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Professor Valter Longo

What if a special diet could reduce inflammation and repair your gut?

USC researchers provided evidence that a low-calorie “fasting-mimicking” diet has the potential to do just that. Published in the Tuesday edition of Cell Reports, the study reports on the health benefits of periodic cycles of the diet for people with inflammation and indicated that the diet reversed inflammatory bowel disease (IBD) pathology in mice.

Results showed that fasting-mimicking diet caused a reduction in intestinal inflammation and an increase in intestinal stem cells in part by promoting the expansion of beneficial gut microbiota. Study authors say the reversal of IBD pathology in mice, together with its anti-inflammatory effects demonstrated in a human clinical trial, indicate that the regimen has the potential to mitigate IBD.

“This study for the first time combines two worlds of research,” said Valter Longo, a study author and the director of the USC Longevity Institute at the USC Leonard Davis School of Gerontology and professor of biological sciences at the USC Dornsife College of Letters, Arts and Sciences. “The first is about what you should eat every day, and many studies point to a diet rich in vegetables, nuts and olive oil. The second is fasting and its effects on inflammation, regeneration and aging.”

Fasting and IBD: Reducing inflammation

By combining these fields of research using the fasting-mimicking diet, the authors were able to reduce the inflammation and pathology associated with intestinal diseases.

Longo said for people with a poor diet, a “once in a while” fix is the periodic use of a low-calorie, plant-based diet that causes cells to act like the body is fasting. Earlier clinical trials conducted by Longo and colleagues allowed participants to consume between 750 and 1,100 calories per day over a five-day period and contained specific proportions of proteins, fats and carbohydrates. Participants saw reduced risk factors for many life-threatening diseases.

“Fasting is hard to stick to and it can be dangerous,” Longo said. “We know that the fasting-mimicking diet is safer and easier than water-only fasting, but the big surprise from this study is that if you replace the fasting-mimicking diet, which includes pre-biotic ingredients, with water, we don’t see the same benefits.”

In the study, one group of mice adhered to a four-day fasting-mimicking diet by consuming approximately 50 percent of their normal caloric intake on the first day and 10 percent of their normal caloric intake from the second through fourth days. Another group fasted with a water-only diet for 48 hours.

The study demonstrated that two cycles of a four-day fasting-mimicking diet followed by a normal diet appeared to be enough to mitigate some, and reverse other, IBD-associated pathologies or symptoms. In contrast, water-only fasting came up short, indicating that certain nutrients in the fasting-mimicking diet contribute to the microbial and anti-inflammatory changes necessary to maximize the effects of the fasting regimen.

“We’ve determined that the dietary components are contributing to the beneficial effects; it’s not just about the cells of the human body but it’s also about the microbes that are affected by both the fasting and the diet,” Longo said. “The ingredients in the diet pushed the microbes to help the fasting maximize the benefits against IBD.”

The research team observed activation of stem cells and a regenerative effort in the colon and the small intestine, which increased significantly in length only in the presence of multiple cycles of the fasting-mimicking diet. They concluded that fasting primes the body for improvement, but it is the “re-feeding” that provides the opportunity to rebuild cells and tissues.

Fasting and IBD: Importance of “refeeding”

“It is really remarkable, that in the past 100 years of research into calorie restriction, no one recognized the importance of the re-feeding,” Longo said. “Restriction is like a demolition where you take the building down. But you have to rebuild it. If you don’t do that, there’s no benefit. You are left with an empty lot, and what have you achieved?”

In the current and previous studies, the authors showed that in patients with elevated C-reactive protein, a marker for inflammation, fasting-mimicking diet cycles are able to reduce C-reactive protein and reverse the associated increase in white blood cells. Together with the results in mice, these data indicate that fasting-mimicking diet cycles have the potential to be effective against human IBD, including Crohn’s disease and ulcerative colitis.

IBD afflicts an estimated 1.6 million Americans and is associated with acute and chronic inflammation of the intestine. Study authors say a randomized clinical trial involving the use of fasting-mimicking diet cycles to treat IBD is necessary to determine the safety and efficacy of these dietary treatments in humans, and are currently finalizing a clinical trial protocol.

Additional authors include Priya Rangan, Inyoung Choi, Min Wei, Gerardo Navarrete, Esra Guen, Sebastian Brandhorst, and Gab Pasia of the Longevity Institute, USC Leonard Davis School of Gerontology and Nobel Enyati of the USC Dornsife College of Letters, Arts and Sciences Department of Biological Sciences.

The study was funded in part by NIH/NIA grants AG20642, AG025135, P01 AG055369, P01 AG034906, and the Glenn Foundation for Medical Research.

Longo is the founder of and has an ownership interest in L-Nutra; the company’s food products are used in studies of the fasting-mimicking diet. Longo’s interest in L-Nutra was disclosed and managed per USC’s conflicts-of-interest policies. USC has an ownership interest in L-Nutra and the potential to receive royalty payments from L-Nutra. USC’s financial interest in the company has been disclosed and managed under USC’s institutional conflict of interest policies.

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