By Dr. Mercola
Your diet can have an enormous influence on how long you live and your likelihood of contracting disease. In this interview, Valter Longo Ph.D., professor of gerontology and biological sciences at the University of Southern California and director of The Longevity Institute, discusses the health benefits of a fasting-mimicking diet.
The fasting-mimicking diet developed by Longo's team is thus named because it affects important disease and aging pathways in your body, such as insulin-like growth factor 1 (IGF-1), IGFBP1, glucose and ketone bodies, in the same way water-only fasting does. Longo has done extensive research in one of my areas of passion, which is optimizing mitochondrial metabolism through dietary interventions. He's also spent many years looking at the health effects of calorie restriction.
"I was a student of Roy Walford many years ago. Roy was one of the pioneers of calorie restriction. He was a medical doctor [who] was very interested in using diet to prevent and even treat diseases. That started back in the early '90s.
Then I went on to turn to a more molecular understanding of what connects each ingredient, what connects each amino acid, the sugars, the fats, the type of fats, to the pathways that we were studying, particularly the pro-aging pathways. Two of them we discovered: the RAS-PKA pathway [and] TOR-S6 kinase. Both have now been shown to be central in the aging process, not just in simple organisms and mice but possibly also in humans," Longo says.
Longo's lab also discovered the role of the target of rapamycin (TOR) pathway in aging and in the protection of cells. (The TOR pathway itself was discovered by Michael Hall.) Understanding the impact of food on this pathway is essential for understanding how to optimize your diet.
Calorie Restriction and Longevity
You've probably heard that calorie restriction has been linked to longevity. However, the scientific evidence for this is still rather weak. Calorie restriction typically refers to cutting calories by 30 to 50 percent on a continuous or consistent basis. According to Longo, most of the long-term studies done on monkeys and other animals have produced questionable results. And, while some studies have found beneficial effects on mortality and diseases, others have not.
"This is why we never really focused on calorie restriction, but tried to get the benefits of calorie restriction and at the same time not the negative effects. That's where these periodic fasting-mimicking diets come from," Longo explains.
There's also the practical challenge of actually applying calorie restriction, as most people simply cannot remain compliant on a general "starvation diet" for years on end.
The Benefits of Fasting-Mimicking Diets
Fortunately, evidence suggests you can get the molecular benefits of long-term calorie restriction by only periodically restricting calories and, more importantly, by restricting mostly proteins and sugars. This includes the long-term effects on GH and IGF-1, one of the factors that regulate growth pathways and growth genes.
IGF-1 seems to be a major player in accelerated aging, and slowing the aging process is one of the effects of Longo's fasting-mimicking dietary intervention. Calorie restriction has also been shown to boost cellular and intracellular regeneration and rejuvenation (autophagy and mitophagy). As far as aging is concerned, IGF-1 and growth hormone are in the same axis, the growth hormone-IGF-1 axis. Studies have shown that IGF-1 and growth hormone receptor deficient mice have record-long lifespans.
"For a number of years, we followed a group of people in Ecuador who are also growth hormone receptor deficient. They have the same or very similar mutation to the mice that have record longevity.
A few years ago, we showed they seem to be protected from cancer and diabetes," Longo says. "We suspect that this protection is also extendable to more diseases. Although they may not be very much longer-lived than their relatives, they seem to be much healthier."
In essence, by optimizing your diet for longevity, you're indirectly preventing most chronic degenerative diseases, and optimizing the IGF-1-growth hormone axis is a key aspect of this.
Effects of Fasting-Mimicking Diet in Mice
While you cannot fast continuously, for life, or remain on a calorie-restricted diet forever, Longo's research shows that when you do calorie restriction intermittently, your body maintains a memory of the metabolic switch that can last a long time. This hypothesis was initially tested in simple organisms and mice, and was found to work very well.
For example, Longo placed middle-aged mice on a periodic fasting schedule in which, twice a month, the mice were placed on a restricted diet for four days. Their diet was relatively high in fats while being restricted in proteins and sugars. So, for eight days a month, they were on a low-calorie, low-protein/low-sugar diet.
The remainder of the time, they ate normally. When the volume of food was averaged out over the month, they were actually not calorie restricted at all, as they made up for the temporary restriction by eating slightly more afterward. Still, these mice had half the tumors of the control group, which had no fasting period. Even when tumors did develop in the treatment group, they developed later and were mostly benign. They also maintained better cognition with age, had less inflammation and a longer mean lifespan.
"They don't have a longer maximum lifespan, and we suspect that is because the very old mice did not like fasting or to be on the fasting-mimicking diet," Longo says.
"It doesn't mean that it may not be beneficial, but I think we have to do more studies, and maybe we need to come up with a higher calorie version of the fasting-mimicking diet, which is now about 50 percent calorie restricted, so that we don't have the good and the bad after [age] 70.
There's no indication that before [age 70] there are any problems. In fact, mice that are fairly old perform very well under fast-mimicking diet, but the very old ones do not."
Effects of Fasting-Mimicking Diet in Humans
In the human trial, fasting was done five days per month for three months. The diet was very low in sugar, relatively high in complex carbohydrates, low in protein (no animal products at all) and high in healthy fats. This type of intervention was enough to put most people into temporary nutritional ketosis, which is when your body starts burning fat as its primary fuel rather than sugar.
From a metabolic perspective, clearance of damaged cell and cell content actually occurs during the fasting phase, much in the same way exercise actually produces damage to your tissues. The "magic" occurs during the refeeding phase, when cells are rebuilt and rejuvenated. Longo explains:
"The process is really comprehensive, meaning almost everything changes … For example, the IGF-1 goes way down, the glucose will go way down, the ketone bodies are greatly elevated. The reason is that the body starts burning fat … primarily the visceral fats. This is a really important point. We really did not see much of a significant difference in the subcutaneous fat.
We saw a significant difference in the abdominal fat, indicating that this is coming mostly from one source. Maybe this is the reservoir where the body goes first when the glucose is not coming in. I think the clearance of damaged cells is also very important.
We've shown this in a mouse and human preliminary multiple sclerosis trial, in which we were able to show that each cycle of the fasting-mimicking diet is able to kill some of the autoimmune cells and then turn on the stem cells and regenerate cells that are no longer autoimmune.
The human trial is still preliminary, but certainly it was very promising. Especially when you consider, like in the mouse [study], we saw a temporary reduction of the white blood cells in the patients. Over 70 percent of the patients had over 20 percent reduction in the white blood cell number. That told us it is probably working in people like it's working in mice.
The system tries to … [kill] off white blood cells, turning on the hematopoietic stem cells. Then when you refeed, and only if you refeed, the stem cells are now giving rise to young and functional white blood cells … [The] human clinical trial supports the notion that this is happening everywhere in the human body."
The Regenerative Benefits of Periodic Fasting
A particularly fascinating aspect is that it also seems to improve stem cell production, which you need to maintain good health. In fact, people undergo stem cell transplantation for a variety of reasons. But it would seem far safer, less expensive, and perhaps even more effective to do it naturally with this kind of dietary modulation.
Longo also points out that when you inject stem cells, the stem cells lack the program that tells them what to do. When you fast, and the level of white blood cells drops, the refeeding phase automatically provides the instructions to rebuild everything that is missing. is expected to be released in the U.S. sometime this summer. The Italian version is titled "The Longevity Diet." The American title is as yet undetermined.
This book details Longo's decades' long research into longevity and aging, describing not only the fasting-mimicking diet but also other diets shown to promote longevity. Overall, a pescetarian, or mostly fish- and plant-based diet low in protein and sugar and high in complex carbs and healthy fats, is the most effective.
"The everyday diet has a lot of similarities with the fasting-mimicking diet, but of course, in a way to allow people to maintain a normal weight, and also maintain high nourishment," he says. "It's about 55 percent complex carbohydrates, 35 percent fats and 10 percent protein, trying to keep the protein above 0.7 to 0.75 grams per kilogram of body weight per day, or 0.35 grams per pound of body weight per day."
That would come out to about 1 gram of protein per kilogram of LEAN body mass, which I believe is a more accurate way to assess your protein requirement. As explained in previous articles, restricting protein to just what your body needs, and no more, is an important consideration that promotes longevity and protects against chronic disease, and this has to do with the way protein influences the mTOR pathway.
The Importance of Limiting Protein
As explained by Longo:
"We published a paper, … showing increased mortality in Americans, particularly cancer mortality in Americans, who had a high-protein diet. This makes sense. One of the reasons it makes sense is that proteins, in particular short amino acids (such as leucine and methionine) are central regulators of these growth factors, particularly mTOR and IGF-1 … and have a pro-aging and also pro-damage effect.
The higher level of protein, the higher level these amino acids, the higher activity of TOR-S6 kinase pathway. As a consequence, we now have very clear evidence in many organisms that TOR accelerates aging and also accelerates mortality, meaning that all kinds of organisms will die earlier and develop many more diseases when they maintain this pathway activated …
A good amount of calories come in from proteins, which we have shown … to be able to largely reverse the protection of normal cells. If you have the fasting-mimicking diet or fasting, and then you give mice a normal level of protein, they can reverse a lot of the protective effect …
The other pathway, which is much less known … is the sugar PKA pathway or RAS/PKA pathway (protein kinase A). Now there is starting to be evidence from our lab and others that this may also be conserved. Meaning that, in addition to the protein pathway, there is also a sugar pathway that is as bad, or almost as bad …
The more sugar there is available, the more the PKA pathway … gets activated. This gene then in turn can inactivate certain transcription factors … that are very important for protection of the cell, but also for the reprogramming of the cell into a more what we call a maintenance state."
Maintaining Protein Adequacy Through Protein Cycling
One of the factors that really intrigues me about Longo's work is his focus on protein cycling. As mentioned, there are significant downsides to excess protein, but too little is hazardous as well. It's important to maintain a balance of "just enough" protein in order to avoid losing lean muscle mass as you age, while still avoiding the activation of TOR, which speeds up the aging process.
Longo's answer to this complexity is to cycle high and low amounts of protein. For example, you could eat 1.5 grams of protein per kilogram of lean body weight on days when you're doing strength training exercises, and then cut back to 1 gram/kilo on non-training days.
"There are a number of groups that are now looking at the relationship between protein and muscle protein synthesis," Longo says. "I think they've clearly shown, for example, that 30 grams of salt proteins are needed in one single meal, associated with strength training, in order for the muscle protein synthesis to occur. I will say that there is an optimal level.
We have also … shown … people that were 65 or younger benefited from the very low protein, but people who were 65 and older did not benefit … Now, the correct study has never been done, meaning there has never been a study where you take 1,000 healthy 80-year-olds and you give them exactly a low level of protein and see how they do compared to the ones that eat 1.5 to 2 grams per kilogram a day. I suspect they will still do better.
[But] there was no evidence in our study that the people [who] had high protein intake, even at older ages, did better. It was sufficient to do the moderate protein intake even in older ages … [T]he pulses are key because that's all that matters. You just have to have enough protein, TOR activation, the building process occurs and then that's long lasting …
They haven't done long-term studies on this, so we don't know the best way. But certainly, the short-term studies indicate that you don't need a very high protein, but you do need sufficient protein and you need the training to optimize the muscle building."
So, in summary, for strength building purposes, the science tells us 30 grams of optimized for branched-chain amino acids combined with strength training is an ideal amount to achieve long-term protein synthesis in the muscle, and more is not better. In fact, while more protein has no beneficial effect on muscle building, it may, however, have an adverse health effect by activating mTOR.
Notably, it is not clear how muscle synthesis would be affected by multiple daily combinations of 30 grams of proteins plus training, but it's likely not a wise strategy if you want to keep mTOR chronically inhibited.
Feast-Famine Cycling
On a personal note, I engaged in long-term (six months or so) chronic nutritional ketosis. But then I started noticing some adverse effects. I think these effects may be related to action of insulin, which many aren't aware of. I then discovered a process I call "feast-famine cycling," which is similar to the protein cycling Longo recommends.
The way insulin works is not by driving glucose into the cells, which is what's conventionally taught. Insulin actually works by stopping the liver's ability to produce glucose (hepatic gluconeogenesis). If you have very low levels of insulin, you're not going to be able to suppress hepatic gluconeogenesis. Paradoxically, your blood sugar will rise pretty dramatically, even though you're not having any carbohydrates.
Interestingly, when you have relatively high glucose level and really low insulin levels, if you eat sugar, your blood sugar drops, which is absolutely counterintuitive. But again, that's related to the mechanism of insulin. This was when the importance of cycling became really clear to me, because you really do want to keep your glucose level low. If you restrict glucose and protein too much, it'll be counterproductive.
So this cycling is absolutely imperative. In fact, I believe feast-famine cycling may be the key to optimizing the molecular pathways involved in chronic disease and longevity. Longo agrees, saying:
"I think you hit it right in the head. Meaning that if you understand the mechanisms, like you just described, this is really important. This is essential. You have to understand exactly what goes on. Because if you don't, you're going to get surprises.
I think maybe you were surprised after six months that you're starting to see problems. I've also seen some of that, for example, in the alternate-day fasting. There are papers showing benefits, but there are some papers showing detrimental effects. It's just up and down, up and down."
How to Increase Your Longevity
As an aging and longevity researcher, Longo offers the following suggestions for those interested in achieving a long and healthy life:
• Overall, a fish- and plant-based diet has the strongest support. The key is to maintain low protein, but sufficient for your current phase of life. As you get older, you need slightly more, but not a whole lot more protein.
• As you age, keep a normal weight and be highly nourished — even if you have to add more ingredients to your diet that you might not have eaten before.
"For example, I talk in the book about cheeses that several of the centenarian population around the world [eat], like goat cheese. You may not have wanted to use frequently when you were younger, but you can use when you're older. Or maybe some yogurt or eggs. Some of these things I exclude before 65 to 70, but then I say, 'They're really very rich in nutrition.' A lot of centenarians do it, so it might be a good idea," Longo says.
• Cycle eating and fasting (time-restricted feeding), 12 hours on and 12 hours off.
• If you're overweight or have a tendency to gain weight easily, eat only two meals a day. (Longo believes most people do need to eat breakfast.) If you don't have a weight problem, you can eat three meals daily. Ideally, make lunch your largest meal of the day, and avoid eating three to four hours before bedtime.
• Take a multivitamin every three days.
"Why every three days? Because probably, [taking it] every day, you will eventually find out that's not good for you," Longo says. "Some studies suggest that. But every three days, it probably eliminates most malnourishment. At the same time, the chance that it does you damage is extremely low, considering how many studies have been done on them and showing usually neutral effects."
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