Fasting Mimetics: Health And Longevity Benefits With Dr. Valter Longo

For many, incorporating a consistent fasting routine might sound scary and far out of reach. Turns out, tricking the body into thinking it’s facing a food scarce phase will trigger even more long-term benefits than keeping calories extremely low for weeks and months at a time. A growing number of studies are finding how fasting mimetics may improve not only overall health but increase lifespan and healthspan too.

We sat down with Dr. Valter Longo, one of the most renowned professors and researchers in the field of fasting mimetics and longevity. In 2018, TIME magazine named him one of the 50 most influential people in health care for his research on fasting-mimicking diets as a way to improve health and prevent disease.

Additionally, Dr. Longo is the Director of the Longevity Institute at the University of Southern California Leonard Davis School of Gerontology, Los Angeles, and the Director of the Longevity and Cancer Program at the Italian Foundation for Cancer Research Institute of Molecular Oncology in Milan, Italy.

What are fasting mimetics?

Fasting mimetics are compounds that mimic the effects of fasting without requiring complete abstinence from food. These compounds replicate the physiological effects of fasting by activating similar molecular pathways.

They trigger processes such as autophagy (cellular recycling), mitochondria biogenesis, stem cell activation, ketogenesis (production of ketone bodies), and the reduction of insulin-like growth factor 1 (IGF-1) levels, along with inhibiting the mechanistic target of rapamycin (mTOR) pathway, which is involved in cell growth and metabolism.

Research conducted at the University of Southern California (USC), including studies led by Dr. Valter Longo, has shown that fasting and fasting mimetics can activate cellular pathways that promote cellular rejuvenation, metabolic flexibility, longevity, and overall health.

One human study out of USC published in Science Translational Medicine found that the fasting-mimicking diet “reduced body weight and body fat, lowered blood pressure, and decreased the hormone IGF-1, which has been implicated in aging and disease.”

The beginnings: starving yeast

In an interview with Healthnews, Dr. Longo said that when he first started to test starving bacteria, human, then yeast, his colleagues thought it was a “boring” project.

“Everybody thought it was the most boring thing that you could think of, even those who studied yeast,” Dr. Longo said. “Back then, we were actually showing that if you starve the yeast, they live a lot longer,” he said, adding that he thought the benefits came from the organism’s fundamental ability to get rid of damaged components and then replace them with good components and cells. The lifespan of yeast extended two to threefold just by starving them.

So obviously, the potential benefits are unlimited and it can be applied to almost anything. And somehow I don't think too many people realize this yet, but it can be very powerful.

Dr. Longo

From yeast to humans

Caloric restriction did wonders to yeast and even had profound results in treating cancer in mice, but translating it over to humans needed some tweaking.

Around 2010, Dr. Longo and his team started a trial at USC Norris Comprehensive Cancer Center with cancer patients. However, when they did the clinical trial including water-only fasting, cancer patients weren’t so motivated to not eat. “They felt cheated,” he recalled. “Asking, ‘Why would you give me water? I have cancer. This is not right.’”

Dr. Longo said that prolonged caloric restriction can be risky.

There were clinics that were doing very long water fasts, two or three weeks. I never agreed with that view because there are a lot of issues with slowing down the metabolism and other risks, <…> So then the idea was to come up with something that will affect longevity in the same way or better than caloric restriction without the pain, difficulties, and the dangers of caloric restriction.

“We went to the National Cancer Institute of the NIH [National Institute on Health] and the National Institute on Aging, and they both funded research on developing a fasting-mimicking diet,” he said, noting that it took five years to complete.

Dr. Longo and his team carefully connected ingredients and molecules in the food to evoke certain physiological regulatory processes and gene expressions. “We put it all together, and we knew we could develop a fasting-mimicking diet that will be equivalent to water-only fasting but will allow the cancer patients to eat,” he remembered. “And sure enough, it worked there.”

Since then, dozens of studies have applied the fasting-mimicking diet to various diseases including type one diabetes, type two diabetes, inflammatory bowel disease, and Alzheimer’s; many others are still ongoing today too.

What is the fasting-mimicking diet?

The fasting-mimicking diet (FMD) involves a specific meal plan that restricts calorie intake for five consecutive days.

It is carefully formulated to provide a precise balance of macronutrients (proteins, carbohydrates, and fats) and micronutrients (vitamins, minerals, and other essential compounds). The composition of the diet is designed to induce a fasting-like state in the body, triggering various cellular and metabolic responses similar to those observed during an extended water-only fast.

During those five days, the calorie intake is significantly reduced, usually to around 40–50% of normal daily caloric intake — 1,100 kcal on day one, then 800 kcal on days two through five. The diet is typically low in protein and carbohydrates but contains a moderate amount of healthy fats. It is also rich in plant-based foods, including vegetables, nuts, and seeds.

Benefits of fasting-mimicking diet

Research studies on both animal models and human subjects have shown promising results regarding the potential benefits of FMD. These benefits include improved metabolic health, reduced inflammation, enhanced cognitive function, and improved organ functions. The FMD is also being investigated for its potential applications in promoting longevity, supporting weight loss efforts, and reducing the risk of age-related diseases.

The only strategy that reliably extends health span in mammals, including non-human primates.

Cell Metabolism

The mice study published in Cell investigated the effects of FMD on gut microbiota and inflammatory bowel disease (IBD) and found a reduction in intestinal inflammation, increased intestinal stem cells, and an expansion of beneficial gut microbiota, all leading to improvements in IBD.

Additionally, another study, in this case in humans, showed that five days of periodic fasting also affected sirtuin gene expression, which had been associated with longevity in animal models.

A human study of 100 participants looked at the effect of three cycles of FMD over the course of three months compared to a control group consuming their normal diet. The study found that the FMD group had reduced body weight and body fat, lowered blood pressure, and decreased levels of the hormone IGF-1, which has been implicated in aging and disease. A post hoc analysis replicated these results and also showed that fasting decreased body mass index, glucose, triglycerides, cholesterol, and C-reactive protein (a marker for inflammation).

In the context of ongoing diabetes trials, that are yet to be published, Dr. Longo highlighted eye-opening outcomes, stating, “We see just remarkable reversal of insulin resistance.” He mentioned two ongoing trials both demonstrating a “70% reduction in drug usage after six to twelve cycles of the FMD in diabetic patients,” adding that the FMD showcased notable effects on insulin resistance.

Fasting mimetics and stem cells

Fasting-mimetic protocols have shown longevity benefits by activating embryonic stem cells that have the ability to turn into any type of cell in the human body and boosting the Yamanaka factors, which are transcription factors discovered by Dr. Shinya Yamanaka and his team in 2006. These factors are capable of reprogramming differentiated adult cells into induced pluripotent stem cells, which have characteristics similar to embryonic stem cells.

To demonstrate this point, Dr. Longo recalled the “Minnesota Starvation Experiment” that took place in the 1940s after World War II. Participants were put on a 20-week semi-starvation diet that revealed interesting findings “one fascinating observation was that the hearts of these individuals shrank by 41%” he said, “however, when they were fed again, within 20 weeks, the hearts returned to their normal size.”

Dr. Longo mentioned. “This [the heart] is completely non-dividing tissue. So they didn't know what was going on.” Researchers began exploring other organs, such as the pancreas, gut, liver, muscles, and kidneys, to understand the underlying mechanisms.

In the pancreas, two of the Yamanaka factors were way up, but only temporarily. And then they gave rise to this embryonic-like program of rebuilding at least parts of the pancreas.

Dr. Longo

Dr. Longo explained that during fasting, stem cells and the Yamanaka factors, responsible for reprogramming cells, become activated. This phenomenon may help regenerate damaged or shrunken tissues.

The shrinking of organs could potentially play a role in clearing out senescent cells and other unwanted molecules. Dr. Longo affirmed, “That's definitely part of it.”

He noted that health regulatory bodies today would never allow such extreme human experiments, but we can achieve similar outcomes by periodically mimicking a prolonged fasted state.

Prolonged fasting vs. fasting-mimetic diet

While fasting has been around for thousands of years in different cultures as a religious practice, various fasting approaches have gained popularity in the Western world recently as a way to enhance one’s lifestyle. They are often called time-restricted eating, intermittent fasting, one-meal-a-day eating, or alternate-day fasting.

Fasting-enthusiasts tend to share exciting stories about cognitive benefits or weight-loss achievements. However, when consistent fasting leads to prolonged calorie restrictions, Dr. Longo said, “It can cause more harm than good.”

When people go on a long-term low-calorie diet, even though they might see benefits at the beginning, they will plateau shortly after. Dr. Longo calls this the “thrifty mode.”

Their metabolism slows down, and their body enters this constant hungry mode, eventually leading to gaining more weight than they had lost.

Dr. Longo

Dr. Longo emphasized the importance of avoiding this rebound effect, explaining why the fasting-mimicking diet is limited to five days — “think of it as a five-day reset.”

“We see accelerated metabolism, so we see a fat catabolic mode,” he noted. The FMD, with its adequate calorie content, signals to the body that it has enough food, preventing excessive fat loss. Dr. Longo explained that FMD promotes a fat-burning mode and insulin sensitivity. Weight loss is a bonus. It’s the longevity benefits that make FMD worthwhile.

Fasting-mimetic pharmaceuticals

Fasting-mimetic drugs are pharmaceutical compounds that typically target pathways involved in cellular stress response, metabolism, and cellular rejuvenation. They may influence processes such as autophagy, mitochondrial function, inflammation, and insulin sensitivity. By modulating these pathways, fasting mimetics aim to promote overall health and potentially offer therapeutic benefits for various conditions.

However, Dr. Longo cautions that while these drugs are proven to have short-term benefits, more research is needed to fully discover how they may impact physiological processes in the long run.

Rapamycin

Rapamycin is an immunosuppressant drug used in transplantation and cancer treatment. It has also demonstrated fasting mimetic properties by inhibiting the mechanistic target of the rapamycin (mTOR) pathway, which is involved in cell growth and metabolism. Activation of mTOR is suppressed during fasting, and rapamycin's inhibition of mTOR can mimic some effects of fasting, such as autophagy induction and protein synthesis.

However, Dr. Longo warns it also causes hyperglycemia.

Could they cause lots of problems in people? Absolutely. We published, for example, that if you give mouse chemotherapy together with rapamycin, you make them a lot more sensitive to chemotherapy because now the hyperglycemia is causing sensitization of the cells, …

Dr. Longo

Metformin

Metformin primarily works by activating the enzyme AMP-activated protein kinase (AMPK), which is a vital regulator of cellular energy metabolism and essential for maintaining balanced levels of glucose and lipids in the body. By activating AMPK, metformin enhances glucose uptake in muscles, decreases glucose production in the liver, and enhances insulin sensitivity in peripheral tissues.

Metformin is the go-to pharmaceutical for type 2 diabetes, and research has found it to have promising outcomes. It’s been used in the pharmaceutical setting for more than 60 years, but more research is needed to explore all the ways it may impact the human body.

Should you try fasting mimetics to promote longevity?

The short answer is yes. According to the World Health Organization, obesity impacts 60% of adults in Europe and this number is close to 75% in the U.S. Therefore, Dr. Longo emphasized the importance of addressing insulin resistance and its connection to obesity and metabolic issues. He explained how these conditions can progress into age-associated diseases such as cardiovascular disease and neurodegenerative disease.

The FMD aims to restore insulin sensitivity, prevent fat accumulation, and mitigate the development of related health conditions.

Dr. Longo

He recommends only reaching for the pharmaceutical interventions if one refuses to try everything else, including the fasting-mimicking diet.

He referred to a meta analysis that reported a 13-year life extension for people who followed a third of what he called the longevity diet. “You're going to live a lot longer on average, and very few people are going to have side effects. We see really no evidence of anybody falling in that category,” he said, adding that everyone can benefit from eating enough protein, the majority from plant-based sources, doing two or three fasting-mimicking diet cycles a year, and exercising 150 minutes a week.

“I think that's what everybody should do. And almost nobody's doing any of this, or at least it's definitely really rare, and we're not going in the right direction,” Dr. Longo said.