Reducing your caloric intake for a period of time — typically a five day stretch every few months — is the single best intervention for extending longevity and fighting disease. So says Dr. Valter Longo, the Edna M. Jones Professor of Gerontology and Biological Sciences and the Director of the Longevity Institute at the University of Southern California-Leonard David School of Gerontology. His career has centered on his Feasting-Mimicking Diet, or FMD: Calorie restrictions over five days to trigger a fasting mode, coupled with a 12-hour window when people can eat. Longer intermittent fasting periods? “A bad idea,” he says.
“People become two and a half years younger,” Dr. Longo said during the “Fueling Longevity: Nutrition and Sleep” session at DOC 2025 with Dr. Tony Masri, neurologist and co-founder and CEO of Helyx Health.
His diet has led to the best-selling book, “The Longevity Diet,” and studies showing how the approach shifts the way the body ages, from reducing insulin resistance to hypertension.
You can hear more from Dr. Longo’s talk in the video, or read our lightly edited transcript below.
TRANSCRIPT:
Valter Longo
If you look at 100 years of longevity research, calorie restriction, which is something very simple, it’s actually if you take a normal calorie diet, and restricted by 25%, the calorie station turns out to be the most successful intervention, I will argue ever to slow down aging but also, combat diseases. The first study on human calorie restriction was done by Dr. Roy Walford, the bold guy at the bottom of the picture. Roy was a medical doctor at UCLA. He was my boss, back in 1992, 93. Roy decided to do the first clinical trial on human calorie restriction.
He locked himself up in this Biosphere 2 area in the desert of Arizona near Tucson. For two years they did a calorie restriction study. So they just reduced calorie intake by 25%. They also had a very healthy diet. But that’s not the ideal of caloric restriction, right? If you look at systolic blood pressure, they’re fairly healthy. A group of eight people, systolic blood pressure drops from 110 to 90. Glucose from 95 to 70. Cholesterol from 185 to 125. You can look at this, and if you’re a cardiologist or a doctor, you say this is great. Then you look at Walford on the left when he came out of Biosphere 2, and you say, if you’re a doctor, this is not so good.
It’s being pushed to the limit. The question is, how do you keep all these incredible effects of calorie restriction really revolutionized medicine, right. If you could change cholesterol, blood pressure and not just inflammation. This calorie restriction really goes after almost anything that you can think of that is bad for you. But it comes with a big cost, including lean body mass loss, bone density loss, potentially immune system. Certainly, dampening of certain functions of the immune system.
Back then, I start thinking how do we keep the good effects of calorie selection without the bad that I just mentioned. So first, I started thinking, can you intervene for just five days, let’s say a fasting once every month or two months or three months and that’s it and then let the person go back to their normal diet. Then can we do it now with water-only fasting. Can you do it with a fasting mimicking diet. That’s where I, thanks to the funding by the NIH, develop a low calorie, low sugar, low protein, high fat, vegan, five day long fasting mimicking diet and without going through the markers.
We are looking for fasting response or response to four markers IGF one, IGF, VP1, glucose and ketone bodies.
The first trial was a USC, 100 patients randomized crossover. You see the on the right is the result after three monthly cycle of a five-day fasting making diet. It’s a major reduction in weight, abdominal fat, waist circumference. But unlike the GLP-1 receptor agonist drugs, you don’t see the absolute lean body mass loss. You see that muscle is preserved, maybe a minor loss, but muscle is preserved. These cycles of FMD are targeting fat without affecting negatively the muscle mass and the bone density also.
It’s interesting differently from the calorie restriction. If you look at just give you a couple examples, glucose in normal subjects there’s a small reduction in glucose. But in pre-diabetic subjects, most pre-diabetic subjects now go back to the normal range. So it’s differential effects which were not seen by calorie restriction. Same thing with cholesterol, with cholesterol below 200, relatively normal, they have a decline after three cycles. The FMD keeps going forward. And those that have, hypercholesterolemia, they have a much larger, benefit after of the three cycles of the FMD.
Now, Heidelberg did actually a trial that on diabetes patients. They compare five days of a Mediterranean diet with five days of a fasting, diet, thinking maybe it’s just a healthy diet if you do once a month, a healthy diet for six cycles, six months, you’re going to benefit.
But as you can see, no effects of the Mediterranean diet on A1C, but also no effect on insulin resistance. But there is a a major, reduction of B1C 1.4%, also a major reduction in insulin resistance. And the most important is diabetes drugs in hypertension, drugs. The FMD is able to allow 70% of the patients to reduce drug use, either the dose or completely get rid of drugs. This is not seen in the Mediterranean diet where you actually see 30% of patients increase the use of diabetes drugs.
Why do we see these effects on hypertension? As I showed you earlier, with even calorie restriction, lots of effects and lots of different systems. We started looking at cellular reprograming. We knew that there is cellular autophagy occurring after fasting. We had shown the stem cell are increased, but we are also very much interested in this reprograming this is probably the hardest thing in aging research, right? Can you turn on these Yamanaka factors and all these embryonic developmental factors and make an old cell young? This is what is now being done by biohacking, by lots of different methods.
A few years ago, we published this paper where we damaged the pancreas of a mouse. You see, in the left at the bottom, you see that red is insulin producing beta cells. Then you see what is D5, a lot of the red is gone. Day 50, it’s permanently gone. We now damaged the pancreas irreversibly. But now after irreversible damage to the pancreas, we start with the cycles of the fasting making diet. You see that? The right, the pancreas goes back to normal. It’s making the insulin producing beta cells are regenerated, and the insulin is produced, and now the hypoglycemia here, comes down on the left up. Why is that? It turns out that you see those, three columns. The first one is the mice are eating normally. The middle one where it says FMD is at the end of the four-day fasting, mimicking that in this case, for mice. You see all these red, red colors. It means that the embryonic developmental genes have been turned on. Now including Yamanaka factors, in a coordinated way, the fasting feed cycles are turning on these regenerative, embryonic developmental, genes and repairing. Now is this systemic or is it just a few organs? We’ve shown for the gut, we’ve shown and for the kidneys we’ve shown it for the pancreas. In collaboration with Morgan Levine, who is now out of the lab, we looked at biological age, what happens after three cycle of the fasting week, diet monthly FMD. It turns out that, People become two and a half years younger at least according to these blood markers, which include cholesterol, blood pressure, A1C-reactive protein.
To the FMD, which is at the very bottom, let’s say one to three to six cycles or so of FMD a year, depending on who you are. Then I wrote a book called “The Longevity Diet,” based on lots of different, parts of science or fields of science, including epidemiological studies, centenarian studies, mouse studies, you know, areas of the world, where people have record longevity. So it’s mostly plant based, plus fish 3 or 4 times a week, low protein until age 65 to 70 and then moderate after lots of legumes, whole grains, vegetables, healthy fats, no red processed meat, low eggs, low sugar, low refined grains. These up to age 65/70. Then most people need to expand. And we think the Mediterranean diet now becomes maybe a better option, just because it’s safer, it’s more nutrients. And so Longevity Diet into 65 then I mean during and after, wine three a week. Fine. Three glasses a week. High nourishment. Eat within 12 hours a day.
A lot of you have heard about, the 16-hour intermittent fasting. It’s a bad idea. We can discuss it later if there are questions about that. But the 12 hours is certainly a very good idea. Not a negative study I’ve ever seen. It doesn’t work as quickly as 16 hours, but it’s much better option, a much easier option. And then if overweight, we recommend we follow a lot of patients in the foundation clinics. We recommend, two meals, plus a snack until you go back to normal weight, and then you can resume your three meals process snack. Thank you.