USC biogerontologist Dr. Valter Longo, founder of the Prolon fasting-mimicking diet, discusses his research on fasting and brain health.
Fasting, particularly intermittent fasting, is trendier than ever, but scientists are finding that short spurts of fasting could potentially repair the brain and prevent Alzheimer’s disease. Dr. Valter Longo, a biogerontologist and cell biologist at the USC Leonard Davis School of Gerontology and founder of the Prolon fasting-mimicking diet, spoke to Being Patient Live Talks previously about how fasting could be the most potent way to activate rejuvenation processes in the body — and lower the risk of disease, including Alzheimer’s.
Longo is internationally recognized as a leader in aging studies and related diseases. He has pioneered studies of prolonged fasting and fasting-mimicking diet, and his work has shed light on the effect of these diets on processes in the body, like stem cell activation and regeneration. Thanks to his work, there have been multiple clinical trials to study the potential benefits of fasting when it comes to cancer, Alzheimer’s disease, diabetes, cardiovascular disease, and autoimmunities.
Longo has also discovered some of the major genetic pathways regulating aging and life-threatening diseases and identified a genetic mutation in men that is protective against several common diseases.
Longo’s book on fasting and the brain — The Longevity Diet — is an international bestseller, translated into over 15 languages, and sold in more than 20 countries around the globe.
As a follow-up to Longo’s Live Talk four years ago, he returns to the series to discuss new brain health animal studies, and new data from clinical trials on the fasting-mimicking diet, including how it could help prevent diseases like Alzheimer’s.
Watch the full conversation here, or read a transcript from the conversation below:
Being Patient: For people who aren’t familiar with fasting, what’s happening inside our bodies to make us feel better by depriving ourselves of food for a limited period of time?
Valter Longo: We come from a history of having lots of food in the summer or whenever the food was available and becoming insulin resistant. The body becomes resistant to insulin and accumulates fat. This still happens, for example, with the emperor penguins at the South Pole, right? They become large and potentially obese, eventually not eating for a couple of months. So now, those couple of months that we used to have now never come. What happens with fasting is that the body goes back to this winter mode. So, we become insulin sensitive again and begin burning fat.
We’ve done a lot of work, particularly in mice, but also a lot of clinical trials now. The mouse work clearly shows this shrinking elimination of many damaged components during the starvation period, but then the stem cells and other programs go to work. When the food comes back around, there’s this remarkable regenerative program that brings the organs and systems back to the ideal condition. In these fascinating refeeding cycles, we see lots of evidence for a fairly sophisticated, embryonic-like program that fixes many things wrong with the system.
Being Patient: Is there any historical association that we know of that, as human beings, we’re not programmed to eat all the time? Is eating in spurts better for us?
Longo: It’s hard to know what happened 20,000 years ago, but we see it with the animals surrounding us in various regions. In the South Pole, North Pole, or the northern areas of Canada, where some of the bears are, it’s difficult to imagine that you will have food all the time.
This is why hibernation came around, right? Hibernation is basically an evolution of a program that allows you to deal with a long starvation period. That’s where we come from very clearly. Most organisms in the world are in starvation conditions. In my early days, I worked with bacteria and yeast. They’re called stationary phase and sporulation states. So most microorganisms, which represent most organisms in the world, are starving most of the time.
Once in a while, they get the food, grow very rapidly, and then go back to starving, potentially for years. That’s also a very different version of that, but it’s also our history.
Being Patient: When you fast, something called autophagy goes on, right? What happens when we deprive ourselves of food for a specific amount of time?
Longo: Yes, there are lots of processes, and autophagy is one of them, and it happens at the cellular level. So, the cell basically goes through a shrinking process itself. The organism shrinks, and lots of things happen, but it basically eats its own components. So, some organelles, proteins, and macromolecules are broken down.
The purpose, of course, is to use them for fuel and to have less mass to worry about, right? If a cell is large, it has to consume more energy, so it eats itself and becomes smaller. In the end, both of them are important to surpass these fasting periods.
Being Patient: With your latest research on disease prevention, especially for Alzheimer’s disease in particular? Are you in the mouse studies phase of research, or have you tested on humans yet?
Longo: For Alzheimer’s, we’re almost done with the clinical trial at the University of Genoa. This was for 60 patients doing the monthly fasting-mimicking diet. Because we were worried about the age of the patients, we also did a ketogenic sort of high-fat supplement. I think it’s going better than we expected regarding compliance.
You know, a three-year-old may struggle with five days of a fasting-mimicking diet, but most people could complete it and get to the end of the study, which is about a year long. We’ll see what the results of the cognitive effects are. The study is currently enrolling the last patients, so we’ll be finished there within six to twelve months.
Being Patient: We had a question asking how you can participate in this fasting study. Are you running other studies?
Longo: We hope after we publish the animal study and this clinical trial, people can read more about it in cell reports. Then, hopefully, we can talk to our colleagues here in Los Angeles and elsewhere to maybe get some funding to do a multicenter study on cognition and Alzheimer’s.
The fasting-mimicking diet and autophagy are causing a real revolution in the brain’s metabolism. Because now, all of a sudden, the brain is forced to use ketone bodies and rewire in a sense. So, we are hoping that all these together may at least be able to help the drugs or do some of the things that the drugs are not able to do. Just because by the time somebody has Alzheimer’s, the brain is in such an advanced stage of dysfunction.
Being Patient: In your animal models research, you actually found that fasting-mimicking diet cycles reduced neuroinflammation. Tell us a little bit about that.
Longo: We have been talking about that for 20 years, and we published a 2001 paper suggesting the peroxynitrite was very toxic and coming from the microglia. It was killing the neurons, right? It went away, and nobody paid too much attention back then. Then one summer, maybe around six or seven years ago, a lot of this started sort of taking more front and center.
So, a lot of people now are saying that it’s just not just us anymore. Back then, it was just a few groups, but now there are many people. It was interesting from our paper, because when we actually said, let’s just do what’s called RNA seek and let’s see all the changes that occur without having an opinion.
Sure enough, you know, many of the changes in the Alzheimer’s mouse models were inflammatory. So there are a lot of genes that were turned on, and they were indicative of inflammation. Then when we did the fasting, mimicking diet, many of these were brought back down. So this is very interesting, right?
It showed us hundreds of genes that were now increasing in the neuroinflammatory domain. In many, these are now back to normal, certainly lowered after the fasting-mimicking diet cycle. So now, this hypothesis is that systemic metabolism is tightly connected with the brain. This is not surprising. Diabetes patients have a 75% increased chance of developing Alzheimer’s. A lot of this has been ignored. To this day, it is viewed by the neurobiology community as an additional thing.
No, I think it’s not an additional thing about the aging process. I think the metabolic dysfunction, together with brain damage and inflammation, that’s where you now progress to Alzheimer’s. So, we were happy to see that we’re going back to exactly this superoxide peroxynitrite, maybe the microglia, and maybe some other immune cells in the brain attacking the wrong things. That’s where we started, and we believe it to be more now to be at the center of the problem and the center of the solution.
Being Patient: Usually, glucose fuels our brain, but ketones are an alternative fuel source for our brains. Should we seek to be in ketosis for longer because that’s better for our brain health, or should we try to switch between the two systems?
Longo: We don’t know, but if we look at the systems of the pancreas, the liver, the gut, you see these programs of shrinking reexpansion that eventually become very sophisticated and able to fix the problem. It’s almost like it’s a program that was always there to understand how to organ back to where it was. So, you got wounded with a knife 20,000 years ago? Well, you could die, or you could survive. If you survive that, everything gets regenerated, right? Or most of it gets regenerated. So then the question is if it knows how to regenerate all of that, is it possible that the brain also knows how to at least partially reset or regenerate itself?
“So, you got wounded with a knife 20,000 years ago? Well, you could die or you could survive. If you survive that, everything gets regenerated, right? Or most of it gets regenerated. So then the question is if it knows how to regenerate all of that, is it possible that the brain also knows how to at least partially reset or regenerate itself?”
So, I think that the ketone bodies become just a player in their message: “we’re starving, this is the moment to shrink.” The brain doesn’t really shrink like all other organs, right? We know, for example, the heart can become 41% lower mass during prolonged starvation. The brain doesn’t do that. We believe this process is starting to change in this program of high ketone bodies, lower glucose using bulk ketone bodies, and glucose as fuel. That’s part of our reset, and attend to look at what’s wrong with it and maybe try to try to fix it as much as possible.
Now, we’re still at the beginning. The question is, can we induce true repair and rejuvenation? That’s more like science fiction, but that certainly sets the stage. For example, in the pancreas, we took a mouse with a damaged pancreas to the point that it is no longer making insulin. Then we started the FMD cycles, and within a couple of weeks, it was making insulin again, right? Whereas the control is permanently damaged pancreas, right? If we can do it in the pancreas and all these other organs, is it possible that we will be able to do it in the brain? I don’t know. But certainly, it’s interesting.
Ketone bodies, like autophagy, are part of a sophisticated program that does more than just two things. People like to talk about one mechanism and make it the whole story. It’s 3 billion years of evolution. I’ve come up with better than ketone bodies or autophagy.
Being Patient: You call the prolonged diet a longevity diet. So, what do we know about prolonging lifespan and fasting?
Longo: Fasting, like calorie restriction, can go either way: it can do lots of good, be neutral, or damage. For example, if people skip breakfast, they probably do 14-16 hours of resident fasting every night and live shorter. This is consistent; there is more cardiovascular disease and potentially more neurodegenerative issues.
So, fasting is not necessarily a good thing. We need to find the type of interventions and the type of fasting that can work. I think the fasting-mimicking diet can make the system younger, and we’re going to publish a paper on that soon.
The fasting-mimicking diet is a reasonable, feasible way to achieve the effects of fasting or a very particular type of fasting for a very defined length. It’s a very sophisticated system, and we must be knowledgeable and respectful of it.
Being Patient: There’s so much hype over fasting today, but how do you know the type or length is right for you? Or what should we be checking?
Longo: That’s why we started two foundation clinics, one in Los Angeles and one in Milan. We have a team that includes PhDs and physicians that work together. They work with the universities, and we do clinical trials. For example, we’re starting a 500 people clinical trial in southern Italy, you know, randomized, and we have another one with all the patients that come in.
In terms of an individual not in a trial, you can do lots of things. I have several books on it, and The Longevity Diet is focused on that. I tried to write the book based on five pillars. So, my point was, let’s not focus on epidemiology and let’s personalize. If you are female and you’re 82 years old, you will do something different than if you’re a male and 19. It’s the same way with nutrition and longevity, right? You need to be followed by a nutritionist, or a registered dietician, as they can see where you are, your age, who you are, et cetera. Then, you know, you act and adjust, right? I encourage people to find out who is the most trained in this area and the most trustworthy.
Being Patient: Even though it should be tailored to individuals and closely monitored by a doctor as you recommend, should fasting be on everybody’s radar to at least practice to a certain extent for brain health and longevity?
Longo: Yes, absolutely. The number should be 12 hours of fasting and 12 hours of feeding, right? So, 8 am to 8 pm, eat within that time window, or nine to nine or 10 to 10, doesn’t matter, as long as you keep it steady. As long as you keep about three or four hours away from the sleep time.
The fasting-mimicking diet has been clinically tested in many studies now, and it’s probably good to consider it at least two or three times a year. Once a universal leading study is published, it’s likely solid evidence. With what I call the longevity diet, a pescatarian diet rich in whole grains, vegetables, and legumes, is a good idea.
I’m giving you some general ideas, but you know best to contact a registered dietician trained, not just any registered data, someone trained in healthy longevity. I started at USC, that program, which is the first program in the nation for registered dietitians that focuses on health span. Any students coming out of the USC program will be trained in at least that. It’s the idea of, “I’m not gonna just be worried about what’s going to happen to you in the next three days or three months, but I’m worried about you all the way until you hopefully make it to 100 and longer.”
Being Patient: For people who haven’t been diagnosed but have a family member with Alzheimer’s or even potentially have two copies of the ApoE4 gene, how should we be thinking about fasting?
Longo: If I had two copies of ApoE4, I would start fighting it as soon as possible, in as tough a manner as possible. I would do the longevity and fasting-mimicking diet every couple of months. I wouldn’t overdo it again because then you could get the opposite. You could start doing damage. You should have somebody watch your lean body mass, your muscle mass, and your bone density. I think it’s a matter of keeping the equilibrium of maintaining everything just enough, but not lower than the threshold. Because if you pass the threshold, your immune system and everything else won’t be doing well. Then, you will have a bigger problem than the solution you just acquired.
Being Patient: In the Prolon literature, it’s recommended to do consecutive months, maybe three fasts, once a month for three months. Does it have to be sequential?
Longo: I separate myself from the company, though I’m the founder of disclosure properties. But I’m talking as a professor. However, if you’re practicing the fasting-mimicking diet, I recommend recycling. All trials have been consecutive because it’s difficult to do other ways. So, every trial so far is done at once a month for three months, and then wait. In the southern Italian trial, we’re going to do the fasting-mimicking diet once every three months. So four times a year, once every three months. So, we’ll see, right? This is the first time that we do it this way. Because once every three months has not been clinically tested, I’d recommend once a month for three months, and then wait, and then maybe six months later, you could do one cycle. Then, at a maintenance level, let’s say do it three times a year.
Being Patient: What’s the reason behind five days? When I did it at the beginning of this year, I felt like three days would have been enough, but four and five were quite hard.
Longo: Your response is a little unusual, right? Most people suffer for the first three days, a little bit, and then and then they are okay. On days four and five, they say, “I could go another two weeks.” Because now you’re in a fully ketogenic mode, rewired, and everything else. I think the five days are important, as three days is probably just beginning to shrink systems and organs and not enough, and maybe the autophagy is just beginning in lots of cells. After five days, not only is there a compliance issue, like in your case, but I think it’s also the risk of a metabolic switch now that you sense prolonged starvation conditions.
That five-day process seems to be the end of the fasting-mimicking components.
Being Patient: When should we check in with you next about the results of a significant trial? When will you know more?
Longo: Within a year, we will have published the results of our current study, and we’ll see the results of our trial in Italy. But we never know when we could start seeing some positive results. We’ll see.
Katy Koop is a writer and theatre artist based in Raleigh, NC.