Chapter 6

Fasting-Mimicking Diets, Weight Management, and Healthy Longevity

AS I MENTIONED EARLIER, IN 1992, when I saw my mentor Roy Walford exit Biosphere 2 after nearly two years of a severe calorie-restricted diet, I looked at Roy and the other seven emaciated Biospherians and thought, “There must be a better way to delay aging and prevent disease.” Ten years later, as I was searching for ways to protect cancer patients while leaving their cancer cells vulnerable to therapy, I remembered the baker’s yeast experiments from my doctoral research at UCLA. Moving yeast cells from a sugar-rich medium into a medium of pure water had protected them from various toxins, and also caused cells to live twice as long. We eventually determined that switching mice from their normal high-calorie diet to water also protected them from damage caused by the same toxins. And since we knew that both humans and monkeys kept on chronic calorie restriction were at risk for side effects—immune system deficiencies, problems with wound healing, extremely low weight, and high levels of stress, to name a few—I wondered: Could the protective effect of short periods of fasting continue after the mice returned to a normal diet? If so, we could design a periodic short-term fast that would be easy to implement. The burden would be minimal, and the timing and frequency would be within the individual’s control. By limiting the period of fasting to four to five days no more than once a month we could also minimize the side effects.

It was a great plan in theory, but when we tested water-only fasting in cancer patients, the three-day trial was not exactly a roaring success. Not because the results were bad—they were in fact very promising—but because the patients, who were undergoing chemotherapy at the time, found it difficult to undergo such an extreme fast, and their doctors and nurses were also very resistant to the idea (see chapter 7 for more on cancer prevention and treatment). So we needed to find a different solution.

In our cancer studies with mice, we had determined that four major changes in the blood need to occur to show that the mouse had entered a protected state as a result of fasting: (1) lower levels of the growth factor IGF-1; (2) lower levels of glucose; (3) higher levels of ketone bodies, the by-product of fat breakdown; and (4) higher levels of a growth factor inhibitor (IGFBP1).

To achieve these results (i.e., to mimic fasting), we fine-tuned a diet low in proteins and sugars and rich in healthy fats. We took advantage of many additional nutritechnologies developed in my lab to ensure proper nourishment and maximum therapeutic effects. We called this regimen the fasting-mimicking diet (FMD), and later developed it into the product ProLon.

When we tested the three-day-long ProLon in sixteen-month-old mice (the equivalent of a forty-five-year-old human), the results were remarkable:

• Their 75 percent lifespan (that is, the age at which 75 percent of the mice were still alive) was extended by 18 percent. Their 50 percent lifespan grew by 11 percent.
• The mice ate the same quantities of food per month as the mice on the non-ProLon diet, yet they lost weight, primarily abdominal fat, without loss of muscle mass.
• Age-dependent loss of bone mineral density dropped.
• Tumors were reduced by nearly half, and cancer onset for the great majority of mice on ProLon was pushed back to twenty-six months (equivalent to approximately seventy years for humans) from the onset at twenty months (equivalent to approximately age sixty in humans) in the group on the normal diet. Furthermore, the abnormal lesions in mice on Prolon tended to occur in no more than two organs, indicating that many tumors were probably benign.
• Skin inflammatory disorders were cut in half.
• In the ProLon group, a stem cell–dependent regenerative process rejuvenated the immune system. Regeneration also occurred in the liver, muscle, and brain. Levels of several types of stem cells increased.
• In three different cognitive tests, old mice in the ProLon group performed better at motor coordination (movement), learning, and remembering than the control group.

Consistent with our ProLon research in middle-age mice, we showed in several other mouse studies discussed in the following chapters that periodic fasting promotes stem cell–dependent regeneration in the immune system, nervous system, and pancreas. The fasting itself destroys many damaged cells, and damageed components inside the cells but it also activates stem cells. Once the mice begin eating again, these stem cells become part of a program to regenerate the organ or system, with the newly regenerated cells bearing characteristics of younger, more functional cells.¹ Additionally, the inside of a variety of cells is partially rebulit as part of a process called autophagy, also contributing to cellular rejuvenation.

6.1. Mice receive FMD twice a month from the age of sixteen months.

6.2. Old mice exposed to FMD show less bone density loss (mgHa) when compared with those in the control group.

6.3. Mice that receive FMD in middle age experience rejuvenation of the immune system.

Effects of ProLon in Humans: A Hundred-Subject Clinical Trial

These remarkable results from the mouse studies prompted us to develop an equivalent fasting-mimicking diet for humans. Unlike the one we had developed for cancer patients (see chapter 7), this FMD would have enough calories, vitamins, minerals, and essential nutrients to require minimal medical supervision.

Abstaining from food is a tradition that goes back thousands of years. Early Christians performed the Black Fast during Lent, Muslims fast during Ramadan, and Hindus set aside one day a week for fasting. While little is known about the frequency of fasting in prehistoric times, it’s certain that periodic prolonged fasting was common among our Paleolithic and Neolithic ancestors. Religious fasting has been all but abandoned in modern times; among Christians, the Lenten practice of forty days of calorie restriction ending in a week of water-only fasting has almost disappeared, and the traditional Ramadan fasting month, meant to be a period of restriction and self-discipline during the day, nowadays is often accompanied by overeating after sunset. But the mere fact that fasting is historically common to most religions supports the idea that fasting is not a fad diet, but part of our history and evolution. However, religious fasting was not and is not done for health reasons, so it was important to identify a length and type of fasting that is in fact beneficial for health, while minimizing the burden and safety concerns associated with fasting. A label that is now widely used by the media is “Intermittent Fasting.” I believe this represents a problematic direction because, like the “Mediterranean Diet” or “eating in moderation” it allows people to improvise and pick and choose periods of fasting that range from 12 hours to weeks, giving the impression that just because they all involve some period of “abstention from food” they are similar or equivalent and all provide health benefits. In fact, they have very different effects. For example, if we consider fasting as the period necessary to switch from a primarily sugar-burning mode to a fat-burning mode, then only periods of abstention from food lasting two or three days or more can be considered fasting. The same length of fasting appears to be necessary to trigger the activation of “regenerative” programs. This does not mean that shorter periods of abstention from food cannot be beneficial, but that we should not use words like “Intermittent Fasting” to include interventions that are very different and have very different effects just like we don’t want to place in the same category walking for fifteen minutes and running a marathon.

We have abundant safety data on long-term fasting from such programs as Northern California’s TrueNorth Health Center and the Buchinger Wilhelmi clinics in Germany and Spain, where thousands of patients a year undergo fasts of a week or longer supervised by medical staff. Because these fasting regimens are either water-only (TrueNorth) or confined to a few hundred calories per day (Buchinger Wilhelmi), it is important to do this in a specialized clinic and under medical supervision. Some doctors and nutritionists offer outpatient fasting support, but this requires expertise and can be dangerous.

By contrast, the five-day FMD was developed with the following goals:

1. To provide sufficient calories to be safe outside of a clinic
2. To provide a variety of components that most people can enjoy
3. To be 100 percent plant-based, as described in the Longevity Diet in chapter 4
4. To be equally effective as fasting, if not more so

The FMD, as demonstrated in our animal studies, treats aging and promotes healthy longevity using the following processes:

• Switching all cells to a protected anti-aging mode
• Promoting autophagy (self-eating of parts of the cell) and replacing damaged cell components with newly generated functional ones
• Killing damaged cells in many organs and systems and replacing them with newly regenerated cells from activated stem cells
• Shifting the body into an abdominal/visceral fat-burning mode, which continues after returning to a normal diet (probably due to epigenetic changes, which are modifications of the DNA and proteins that bind DNA)

Our randomized study of one hundred patients carried out at the USC medical center yielded impressive results. Participants who adopted an FMD for five days a month over a period of three months showed remarkable outcomes in the following areas:

Weight loss	More than 8 pounds in obese subjects, much of that from shedding abdominal fat
Muscle mass	Increased relative to body weight
Glucose	12 mg/dL decrease in subjects with high fasting-glucose (prediabetic) and a return to the normal range for prediabetic subjects; no effect in participants with low fasting-glucose
Blood pressure	6 mmHg decrease in subjects with moderately high blood pressure, but not in subjects with low blood pressure
Cholesterol	20 mg/dL decrease in participants with high cholesterol
IGF-1 (associated with a high cancer risk)	55 ng/mL decrease in participants in the higher-risk range
C-reactive protein (CRP; a risk factor for cardiovascular disease)	1.5 mg/dL decrease and, in most cases, a return to normal levels in participants with elevated CRP
Triglycerides	A 25 mg/dL decrease in participants with high triglycerides

6.4. Reduction in risk factors for diabetes, cancer, and cardiovascular diseases after three cycles of the FMD (one hundred subjects randomized clinical trial)

Three months after the last ProLon FMD cycle, test subjects still benefited from a significant loss of body fat and reductions in waist circumference, glucose levels, IGF-1, and blood pressure, all of which suggests that the use of the FMD every three months may be sufficient to reduce the risk of a number of diseases.

Awakening the Rejuvenation from Within

If a forty-five-year-old couple can have a near-perfect baby, then clearly the adult body holds all the information necessary to generate a new and viable set of cells, organs, and systems without transferring any of the damage present in the original oocyte and sperm cell. But is it possible to trigger the same regenerative process within adult organisms?

6.5. The sperm cell and egg of a couple in their forties can create a perfect baby.

Perhaps I’m biased because it was my group that discovered its beneficial effects, but I believe the FMD is probably the best way to start this regenerative and self-healing process, with minimal or potentially no side effects (see my TEDx talk, “Fasting: Awakening the Rejuvenation from Within,” on YouTube). The randomized clinical trial results outlined above were achieved in just three months after three cycles of five-day FMD using human subjects. The findings are in keeping with our mouse studies, which showed that FMD acts by breaking down and regenerating the inside of cells (autophagy) and killing off and replacing damaged cells (regeneration). In fact, both in humans and mice, we detected a transient elevation of circulating stem cells in the blood during FMD, which may be responsible for the regeneration and rejuvenation occurring in multiple systems.

By feeding people a very specific diet that tricks the organism into a starvation mode, most organs and systems eliminate unnecessary components (proteins, mitochondria, etc.) but also kill off many cells. As a result, the organism saves energy because it needs to maintain fewer and less active cells. In addition, both cells that are killed and cellular components broken down by autophagy can provide energy to other cells. A good analogy is to think of the body as an old wood-burning steam locomotive low on wood. To reach the next fueling station, the fireman can start burning the train’s oldest and most damaged wooden seats and walls, making the train lighter while generating the steam needed to keep it going. Just as the seats can be rebuilt once the train reaches the fueling station, the streamlined cells, systems, and organs can be rebuilt by activating stem or progenitor cells and activating repair and replacement systems inside the cell to cause regeneration—once the body resumes normal feeding patterns.

6.6. Blood stem cells in patients during FMD

FMD Versus Drugs and Stem Cell–Based Therapies

Many promoters of alternative medicine avoid traditional medicine and even new technologies entirely. Similarly, many doctors and scientists searching for new therapies avoid alternative and natural interventions at all costs. This is a mistake on both sides, and will often mean that a therapy or preventive measure is only partly effective.

In chapter 7, I show how the combination of nutritional strategies and conventional therapies is the most effective for treating cancer in mice, with high potential to achieve the same in humans. My lab has begun to demonstrate the benefits of this mixed strategy for humans as well. However, the potential promise of effective drugs and stem cell–based therapies for other diseases and conditions shouldn’t be an alternative to leading a life of good nutrition and other natural interventions to promote self-healing and self-preservation, since ideally drugs and more aggressive treatments should be used only when natural interventions are not enough. The reason for this is that natural interventions are the result of billions of years of evolution and in many cases can be highly coordinated and minimize or eliminate side effects, whereas drugs or other therapies will have side effects, some of which won’t be detected until years after the beginning of treatment.

Statin drugs, for example, lower cholesterol by reducing the activity of the cholesterol-producing enzyme HMG-CoA reductase. But this approach is a Band-Aid solution that, instead of fixing the original problem at its source, simply reduces one of the negative symptoms generated by the problem. I once asked a cholesterol expert, “Why do some people’s bodies produce much more cholesterol than they need? What is the body trying to do?” Both surprised and annoyed, he replied, “I don’t know. It just does.”

Organisms don’t waste precious resources generating molecules they don’t need. The right therapy for high cholesterol and cardiovascular disease is not to block generation of this molecule, but to find out what is not functioning properly in the body and what command the system is responding to when overproducing cholesterol, so that the problem can be fixed at its foundation. Simply blocking the generation of cholesterol is like adding coolant to an overheated car engine—it will undoubtedly help, but the underlying engine problem remains, and eventually the car will break down. Indeed, an analysis of eleven randomized studies found that taking statins does not change one’s risk of dying.² The same is true for the great majority of drugs, whether they target glucose, cholesterol, or blood pressure levels: they don’t fix the problem; they merely try to limit the damage it causes. Sometimes they work very well and can save or prolong lives. But often they represent a partial solution that creates new problems. This is why, as I pointed out in earlier chapters, biologists, physicians, and dietitians should work together in teams using their respective problem-solving skills to have an immediate and long-term impact on patients. My own lab has been working for years with medical doctors, and we hope this will become the clinical standard someday.

Take, for example, a forty-five-year-old person with slightly elevated cholesterol, a fifty-five-year-old man with mild hypertension, or a woman whose grandmother died of breast cancer at age eighty-five; these kinds of high risk factors can likely be reduced or reversed with a combination of the longevity diet described earlier and a periodic FMD, according to findings emerging from our clinical studies. This can forestall or even eliminate the future need for drug or stem cell therapies or may allow the use of lower levels of drugs. The major advantage of the FMD approach—compared with drug interventions and stem cell–based therapies—is that it awakens a highly coordinated response that is already built into the body but that has fallen dormant because of our steady and constant consumption of food. At present, FMD represents perhaps the safest and most potent way to reverse many age- and diet-related problems by fixing or replacing, and thereby rejuvenating, cells, systems, and organs in a natural way.

FMD achieves this by taking advantage of billions of years of evolution to activate a self-healing program resembling the embryogenesis process (i.e., the normal growth of a fetus). We have demonstrated this in mice and human cells. For example, we were able to cause severe damage and insulin deficiency in the pancreas of both mice with type 1 and type 2 diabetes and show that FMD cycles promote the regeneration of pancreatic cells to restore insulin production.³ As described earlier in the chapter, FMD cycles also reduce fasting glucose and return prediabetic subjects to the normal glucose range. As pointed out below, in participants with normal blood pressure, glucose, cholesterol, and inflammation, we did not find big changes in the level of risk factors in response to three monthly cycles of the FMD, but we saw significant changes among those with the highest levels of risk factors before beginning the FMD. This is consistent with a rejuvenation effect—a true reversal of the physical damage or underlying problem, not simply the blockage of cholesterol synthesis or lowering of glucose levels achieved with statins or diabetes drugs.

6.7. The rejuvenating effects of the FMD

The Fasting-Mimicking Diet

What follows is a simplified version of the FMD tested in our clinical study of one hundred patients at Keck Medical Center of USC and now also recommended to patients by thousands of US and UK doctors. At least ten thousand patients have undergone the ProLon FMD therapy, and there have been no reports of major side effects. The goal in this section is to provide general information that you can take to doctors and dietitians for help implementing the diet, rather than specific recipes for readers to implement on their own. The FMD clinically tested and commercialized by L-Nutra is far more complex than what I describe below, and it includes a precise formula with ingredients that cannot generally be found in stores, as well as instructions on dosages of specific ingredients based on the weight of the patient undertaking the diet. For safety and efficacy reasons, it is strongly recommended that patients do the ProLon FMD and not a “homemade” version of it, which could be ineffective and potentially harmful. L-Nutra is assembling a network of doctors and registered dietitians who specialize in these integrative therapies. Further information and resources are available at www.prolonfmd .com and on my Facebook page, @profvalterlongo. (As pointed out earlier, I do not benefit financially from the sale of ProLon.)

WHO MAY DO THE FMD

• Healthy adults in the normal weight range between the ages of eighteen and seventy years may undertake the FMD. A few genetic mutations, however, are incompatible with long-term fasting. If any side effects occur other than slight weakness, tiredness, or a headache, you should contact your doctor. Drink a small quantity of fruit juice for immediate relief.

WHO MAY NOT DO THE FMD

• Pregnant women.
• People who are underweight, have very low body mass index, or suffer from anorexia.
• People over the age of seventy, unless in superior health—and then only with a doctor’s approval.
• Anyone who is fragile.
• People with liver or kidney diseases.
• People affected by pathologies, unless they have the prior approval of their specialized doctor. In the case of serious or relatively serious illnesses (cancer, diabetes, or cardiovascular, autoimmune, or neurodegenerative diseases), it is important to seek permission and approval from a disease specialist as well as from a dietitian with expertise in the FMD or in therapeutic fasting. The use of the FMD for disease treatment should for the moment be limited to clinical trials unless the doctor determines that there are no other viable options and the patient cannot wait until the conclusion of appropriate clinical trials and FDA approval.
• Patients who take medication should not undertake the FMD without the approval of their doctor with input from a dietitian or doctor who specializes in the use of the FMD. Although it may be possible to combine the FMD with many drugs without side effects, the combination of the FMD and certain drugs could result in severe side effects.
• Patients who have low blood pressure or who are taking medication for hypertension should not undertake the FMD without the approval of a specialized doctor.
• Patients with rare genetic mutations that block the organism’s capacity to produce glucose from glycerol and amino acids (gluconeogenesis).
• Athletes during training or competition. High muscular effort requires levels of glucose not available in the blood during the FMD, leading to a risk of fainting.

OTHER WARNINGS

1. The FMD can never be undertaken in association with insulin or medication that reduces sugar levels. The combination could be lethal. At the end of the FMD, the patient may still be sufficiently insulin-sensitive to have below normal levels of glucose in his or her blood. Because the use of the FMD on diabetic patients could be dangerous, we advise to do it only as part of a clinical trial. Information about upcoming clinical trials can be found on my Facebook page, @profvalterlongo.
2. Do not combine the FMD with very hot and lengthy showers, especially during hot weather. There could be a risk of fainting.
3. Drive with caution—or better yet, don’t drive at all—until you know how the FMD affects you.
4. We advise undergoing the FMD in the presence of another person.

HOW OFTEN TO UNDERTAKE THE FMD

This is a decision that ideally should be made with input from a doctor or registered dietitian, but broad guidelines are as follows:

1. Once a month for overweight or obese patients with at least two risk factors for diabetes, cancer, or cardiovascular or neurodegenerative disease
2. Once every two months for average-weight patients with at least two risk factors for diabetes, cancer, or cardiovascular or neurodegenerative disease
3. Once every three months for average-weight patients with at least one risk factor for diabetes, cancer, or cardiovascular or neurodegenerative disease
4. Once every four months for healthy patients with a normal diet who are not physically active
5. Once every six months for healthy patients with an ideal diet (see chapter 4) who engage in regular physical activity

WHEN TO START THE FMD

• Many people decide to start FMD on a Sunday night so they can end the following Friday night. This decision is based purely on social considerations, allowing them to return to the transition diet on Friday night and to a normal diet on Saturday night.

PREPARATION

• For at least one week before the FMD, we recommend following the Longevity Diet, with 0.36 grams of protein per pound of body weight per day, preferably obtained from vegetables and fish. Multivitamin supplements of omega-3 should be taken at least twice during this preparatory week (see chapter 4).

The FMD

Day 1

1,100 calories

• 500 calories from complex carbohydrates (vegetables such as broccoli, tomatoes, carrots, pumpkin, mushrooms, etc.)
• 500 calories from healthy fats (nuts, olive oil)
• 1 multivitamin and mineral supplement
• 1 omega-3/omega-6 supplement
• Sugarless tea (up to 3 to 4 cups per day)
• 25 grams of plant-based protein, mainly from nuts
• Unlimited water

Days 2–5

800 calories

• 400 calories from complex carbohydrates (vegetables such as broccoli, tomatoes, carrots, pumpkin, mushrooms, etc.)
• 400 calories from healthy fats (nuts, olive oil)
• 1 multivitamin and mineral supplement
• 1 omega-3/omega-6 supplement
• Sugarless tea (up to 3 to 4 cups per day)
• Unlimited water

The above components can be divided between breakfast, lunch, and dinner, or they can be taken as two meals and a snack.

Day 6

Transition diet

For 24 hours following the end of the five-day FMD, patients should follow a diet based on complex carbohydrates (vegetables, cereals, pasta, rice, bread, fruit, etc.), and minimize the consumption of fish, meat, saturated fats, pastries, cheeses, milk, etc.

WHAT TO EXPECT

SIDE EFFECTS

1. Some people feel weak during parts of the FMD. Others say they feel more energetic.
2. Some patients complain of light- or average-intensity headaches. This effect is usually greatly reduced by day 4 or 5, and eliminated entirely by the second or third FMD cycle.
3. Most people feel hungry during the first few days of the FMD. This effect is greatly reduced by day 4 or 5 and on all days during the second or third FMD cycle.
4. Some people suffer a slight backache that disappears once they resume a normal diet.

POSITIVE EFFECTS

In addition to the production of stem cells, the reduction of abdominal fat, and lower levels of risk factors for various illnesses, many people report the following beneficial effects during or after FMD:

1. Glowing skin, which many describe as “younger looking.”
2. Stronger mental focus.
3. An ability to resist bingeing once they resume a normal diet. Many reduce their consumption of sugar and calories, and are less prone to excess in their consumption of coffee, alcohol, desserts, etc.

Now that you understand the Longevity Diet and how and why it works, and the basics of the FMD, I will go into detail in the following chapters on how this program can have profound effects when it comes to preventing, delaying, treating, and even reversing specific diseases. The next five chapters contain more detailed information on the work I and my fellow researchers and physicians around the world are conducting into the potent links between diet and disease, and they are especially intended to help those individuals at high risk for or suffering from cancer, diabetes, cardiovascular disease, neurodegenerative disorders (especially Alzheimer’s), and autoimmune diseases. It is my hope that this book can help as many people as possible take control of their health so that they can supplement the standard care they are receiving with this integrative, inexpensive approach. First up, some remarkable results involving cancer.