Fast Your Way to Better Health — Or Trick Your Body Into It: Recent Research on Fasting-Mimicking Diets and Caloric Restriction

Dating back to the 5th century BCE, when the infamous Greek physician Hippocrates recommended forgoing food to favor health in cases of illness, fasting has been utilized for millennia to support healing, mental clarity, and physical or spiritual rejuvenation. Now, we know that restricting food for periods of time also benefits an extension of both lifespan and healthspan — the years of life lived disease-free. 

Although we know that eating too much food too often contributes to poor health outcomes and excess body weight, fasting requires a certain willpower and dedication that not all of us possess. This has led researchers to wonder if there is a simpler way to reap the benefits of fasting without having to fight hunger pangs all day — and a periodic fasting-mimicking diet (FMD) may be the answer. While FMDs aren’t a complete walk in the park, as they still require a hefty caloric reduction, this diet is specifically formulated to trick the body into a fasting state — plus, you only have to follow the diet for five days out of the month!  

However, this exact form of periodic fasting has only been around for five years — compared to Hippocrates’ 2500 years ago — meaning its clinical research is in its infancy, and scientists still aren’t entirely sure how exactly fasting works in the body. Now, in a recent study published in Nature Metabolism, researchers from USC show that FMDs bolster health and longevity in mice, essentially reversing the detrimental effects of an unhealthy diet and adding to the evidence that a little bit of fasting goes a long way.

The Basics and Benefits Behind a Fasting-Mimicking Diet 

Created by Dr. Valter Longo, a prominent Italian researcher specializing in fasting and the mechanisms of aging, the fasting-mimicking diet only alters food intake for just five days per month. During that one-sixth of the month, the FMD restricts calories by about half and focuses on plant-based foods that are lower-carbohydrate, moderate-protein, and higher-fat. This regimen is designed to mimic the underlying mechanisms of fasting, including autophagy, IGF-1 and mTOR signaling, and the AMPK pathway — let’s take a closer look at what these processes entail. 

• Autophagy: Essentially an internal housecleaning and recycling system, autophagy is our body’s way of clearing out dysfunctional or damaged cells, cell parts, and proteins. A reduction in autophagic ability goes hand in hand with aging and its associated conditions, while boosting autophagy is often linked to longer health- and lifespans. Both caloric restriction and fasting activate this process.


• IGF-1 and mTOR Signaling: IGF-1 and mTOR are, respectively, hormones and proteins necessary for growth and metabolism. However, their overactivation is linked to aging and disease. Fasting is known to reduce IGF-1 and mTOR signaling; the FMD does the same by limiting protein, calories, and carbohydrates that spike blood sugar. Blocking mTOR activity also allows autophagy to do its cell-clearing job better. 


• AMPK Pathway: AMPK is an enzyme that acts as a sensor for low levels of energy, or ATP, inside cells. When this occurs, AMPK works quickly to restore intracellular energy levels, acting as a “metabolic master switch” in the body and stimulating the creation of mitochondria — our cells’ energy powerhouses. The fasting-mimicking diet activates AMPK by limiting energy in the form of calories. 

Trick-or-Treat: Tricking the Body Reaps Sweet Rewards 

With these factors in mind, Longo’s research team wanted to know if employing the 5-day FMD cycle once per month for two years could prevent or reverse the adverse effects of a high-fat, high-calorie diet on healthspan and lifespan in mice. The short answer? It does.

This study looked at three groups of mice — a control group eating regular food, with a second group that ate a high-fat, high-calorie diet (HFCD), similar to a typical Western diet. The third group of mice ate the same unhealthy HFCD diet  for most of the month, followed by five days on the FMD and two days of a regular, healthy diet. While the HFCD mice quickly became obese, the mice on the 5-day FMD cycle maintained healthy weights and body fat percentages, similar to those of the control mice. Additionally, the FMD diet did not cause a reduction in lean body mass, which other methods of fasting or caloric restriction tend to do.   

The FMD also prevented mice from developing poor heart function and high cholesterol, blood sugar, blood pressure, and liver enzymes, all of which are caused by unhealthy diets and contribute to adverse health outcomes. Notably, the mice on the FMD were rescued from the shortened lifespan that the unhealthy mice had. While the HFCD mice had median lifespans of 570 days, the FMD group lived up to 732 days — almost as long as the 836 days seen with the control mice. 

The FMD-cycling mice also exhibited significant changes in gene activity, including activation of genes related to weight loss and metabolizing fat cells. Dr. Longo reports, “Even after the mice in [the] experimental group went back to their high-fat, high-calorie diet, the improved fat breakdown in their bodies continued for a fairly long period.” He continues, wondering, “Is there a similar sweet spot for humans, where you can intervene for a few days and still keep breaking down fat for several weeks?”   

Longo concludes, “The study indicates that it’s possible for mice to eat a relatively bad diet that is counterbalanced by five days of a fasting-mimicking diet. Our major discovery is that intervening with this diet made their hearts more resilient and better functioning than the mice who only ate a high-fat, high-calorie diet.”  

But, the researchers are quick to caution that, although the FMD may counteract an unhealthy diet, they certainly don’t recommend binging on high-calorie, high-fat foods for 25 days of the month. However, this method of eating could facilitate better health in people who are either unwilling or unable to change their diets on an everyday basis.   

Fasting Vs. Caloric Restriction: Who Wins?

While the results of Dr. Longo’s study are undoubtedly supportive of the health and longevity benefits of monthly 5-day fasting-mimicking cycles, other researchers have wondered where exactly these benefits come from — is it the caloric restriction or the prolonged period in between meals that provide the advantages? 

In another study that came out this month in Nature Metabolism, a research team based out of the University of Wisconsin–Madison looked at just that. Authored by Pak and colleagues, the results show that the process of fasting is, in fact, required to experience the full range of benefits — meaning, simply reducing calories but eating all day long is not enough to do the trick.

In a series of experiments with mice, the Wisconsin-based team looked at whether prolonged daily fasting (without reducing overall calorie intake) caused the same effects as caloric restriction, with or without fasting. To tease out the differences between these ideas, the research team split young mice into four groups: a control group who ate a normal diet, a second that ate the full amount of calories but all within 3 hours of the day (“TR”), and the third and fourth, which both had calories reduced by 30%, but one group ate just once per day and fasted the rest (“CR”), while the other ate three meals spread out throughout the day (“MF”). 

While all three of the experimental diets led to weight and fat loss, only the mice who were either calorie-restricted plus fasting, or fasting for most of the day (“CR” and “TR”, respectively) experienced significant benefits to blood glucose (sugar) control and sensitivity to the hormone responsible for blood glucose stability. This suggests that prolonged fasting between meals, not the reduction in calories, is what mediates this improvement in metabolic control. 

Pak and colleagues then looked at the effects of fasting and caloric restriction in older mice, finding that those in the CR group, who only ate once per day, did not show the typical signs of frailty and aging that the control mice did. In addition to maintaining shiny and colorful fur coats, the CR mice also had improvements in long-term memory. Lastly, combining caloric restriction with fasting extended lifespan, with the CR mice having approximately a 20% boost in longevity. Surprisingly, older mice that ate fewer calories but never fasted died even earlier than the control mice that ate as much as they wanted, suggesting that calorie restriction alone without a fasting period may be detrimental.

Fast Your Way to Better Health — Or Trick Your Body Into It

Both of these October 2021 studies are essential stepping stones in the world of fasting and longevity research. In the first, Dr. Longo’s team exhibits how we can trick our bodies into fasting without actually having to do the work day in and day out, enabling the less-disciplined of us to reap these health- and longevity-related rewards.  The second study, authored by Pak and colleagues, provides evidence that caloric restriction alone is insufficient to improve healthspan and lifespan, and a prolonged period of fasting is required — or at least a diet that mimics fasting, like the FMD.

As the senior author of the second paper, UW­ School of Medicine and Public Health metabolism researcher, Dr. Dudley Lamming, reflects, “If fasting is the main driver of health, we should be studying drugs or diet interventions that mimic fasting rather than those that mimic fewer calories.” The Wisconsin-based authors conclude in their paper, “If our findings apply to humans, sharply limiting the portion of the day during which food is consumed may maximize the healthspan and longevity benefits of CR, and may promote healthy aging without requiring a reduction in calorie intake.”

References: 

Mishra, A., Mirzaei, H., Guidi, N., et al. Fasting-mimicking diet prevents high-fat diet effect on cardiometabolic risk and lifespan. Nat Metab 3, 1342–1356 (2021). https://doi.org/10.1038/s42255-021-00469-6

Pak, H.H., Haws, S.A., Green, C.L. et al. Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice. Nat Metab 3, 1327–1341 (2021). https://doi.org/10.1038/s42255-021-00466-9