Calorie restriction (CR) has been shown to promote healthy aging in different species. But new research headed by University of Wisconsin-Madison (UW) researchers suggests that in mice, reduced calorie intake alone is not enough; fasting is essential to derive the full benefit.

The researchers discovered that, combined with eating less, fasting reduces frailty in old age and extends the lifespan of mice. And while the team found that fasting alone can improve blood sugar and liver metabolism, surprisingly, mice that ate fewer calories but never fasted died younger than mice that ate as much as they wanted. This suggests that calorie restriction alone may be harmful.

The new findings lend support to preliminary evidence that fasting can boost health in people, as trends like intermittent fasting continue to hold sway. And evidence from such human and animal studies has added to the growing picture of how health is controlled by when and what we eat, not just how much. “We need to know whether this fasting is required for people to see benefits,” said Dudley Lamming, PhD, a UW­ School of Medicine and Public Health metabolism researcher.

Lamming, together with graduate student Heidi Pak and colleagues at UW–Madison and other institutions, reported on their findings in Nature Metabolism, in a paper titled, “Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice,” in which they concluded,” … our work demonstrates that daily prolonged fasting has powerful health benefits and underlies many benefits of a CR diet in mice, and that while ‘you are what you eat,’ it is equally true that ‘you are when you eat.’”

Over the last few decades, scientists have discovered that long-term calorie restriction provides a wealth of benefits in animals, including lower weight, better blood sugar control, even longer lifespans. “CR is the gold standard for geroprotective interventions, extending lifespan and healthspan in diverse organisms and preventing or delaying many age-associated diseases,” the authors wrote.

Researchers have largely assumed that reduced food intake drove these benefits by reprogramming metabolism. But scientists have also started to realize how previous studies had unintentionally combined calorie restrictions with long fasts by providing animals with food just once a day. “It has recently been realized that CR regimens, as typically implemented in the laboratory, not only restrict calories, but also impose a prolonged daily fast, as CR animals rapidly consume their entire daily meal within ~2 h, and then fast for ~22 h until their next meal,” the team continued. “These findings complicate the interpretation of rodent CR studies … which collaterally imposes fasting.”

Lamming, who has long studied the effect of restricted diets on metabolism, further pointed out, “This overlap of treatment—both reducing calories and imposing a fast—was something that everybody saw, but it wasn’t always obvious that it had biological significance. It’s only been in the past few years that people started getting interested in this issue.”

To look at these factors individually, Lamming’s group designed four different diets for mice to follow. One group ate as much as they wanted whenever they wanted. Another group ate a full amount, but in a short period of time—this gave them a long daily fast without reducing calories. The other two groups were given about 30% fewer calories either once a day or dispersed over the entire day. That meant that some mice had a long daily fast while others ate the same reduced-calorie diet but never fasted, which differed from most previous studies of calorie restriction.

The results indicated that many of the benefits originally ascribed to calorie restriction alone—better blood sugar control, healthier use of fat for energy, protection from frailty in old age, and longer lifespans—all required fasting as well. Mice who ate fewer calories without fasting didn’t see these positive changes. Conversely, fasting on its own, without reducing the amount of food eaten, was just as powerful as calorie restriction with fasting, and was enough to improve insulin sensitivity and to reprogram metabolism to focus more on using fats as a source of energy. The livers of fasting mice also showed the hallmarks of healthier metabolism.

“We found that a reduction of calories without the imposition of a prolonged fast improves glucose tolerance and body composition,” the team stated. “However, prolonged fasting was necessary for CR to improve insulin sensitivity, a key physiological hallmark of the CR response in mammals; alter fuel utilization patterns and increase fatty acid oxidation; and reduce age-related frailty.”

And while the mice that ate fewer calories without ever fasting did show some improved blood sugar control, they also died younger. Compared with mice that both ate less and fasted, these mice that only ate less died about eight months earlier on average. “That was quite surprising,” said Lamming, although other studies have also shown some negative effects from restricting calories.

The team, in addition, measured frailty through metrics like grip strength and coat condition. “In addition to their shorter lifespans, these mice were worse in certain aspects of frailty, but better in others,” Lamming noted. “So, on balance their frailty didn’t change much, but they didn’t look as healthy.” The researchers did not study the effect of fasting alone on lifespan or frailty as mice aged, but other studies have suggested that fasting can provide these benefits as well. The primary studies were done in male mice, but Lamming’s lab also found similar metabolic effects of fasting in female mice.

The research reveals how difficult diet studies are, even in a laboratory environment. That difficulty is magnified for human studies, which simply can’t match the level of control possible in animal models. The newly reported study may help to provide direction to future work trying to answer whether fasting improves human health. “Our work challenges long-standing assumptions about CR, the team commented. “Our results shed new light on how both when and how much we eat regulate metabolic health and longevity, and demonstrate that daily prolonged fasting, and not solely reduced caloric intake, is likely responsible for the metabolic and geroprotective benefits of a CR diet.”

Lamming also noted, “We need to know whether this fasting is required for people to see benefits. 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.”