This article covers some of the advances of recent years in understanding the effects of varied forms of calorie restriction in humans. Efforts to quantify the results and find a good 80/20 point, at which most of the effects of longer and more stringent reductions in calorie intake are still evident, have resulted in practical outcomes. A number of quite interesting discoveries have been made along the way, such as the ability of longer fasting periods to clear out and replace damaged immune cells to some degree.
The second phase of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE 2) trial demonstrated that it's feasible for humans to limit calories for an extended period. In addition, participants who cut back on calories lost weight and kept it off for the duration of the study. There were no adverse effects on quality of life and the participants netted improvements in blood pressure, cholesterol, and insulin resistance - all risk factors of age-related diseases. Significant changes in the study's primary end points -resting metabolic rate and core body temperature - didn't materialize, however. These two factors are believed to slow aging in animal models of caloric restriction.
Scientists have known since the 1930s that restricting calories by roughly 20% to 50% without malnutrition dramatically extends the healthspan and lifespan of some strains of rodents, and in the decades that followed, caloric restriction has been shown to increase the healthy lifespan of creatures ranging from yeast to guppies to monkeys. It's still an open-ended question whether dietary intervention - or any intervention at all - can dramatically extend humans' maximum lifespan. But epidemiological evidence and cross-sectional observations of centenarians and groups that voluntarily cut their calories strongly suggest that the practice could help people extend their average lifespan and live healthier, as well. While participants in the CALERIE 2 trial did benefit from the intervention, they likely would have had better results had they achieved a full 25% reduction in calories.
"You can prescribe whatever you want, but it's another story to have the people following that religiously." Having come to terms with this reality, scientists have been seeking more practical approaches. They've increasingly become interested in fasting-based analogues to daily caloric restriction, such as intermittent or alternate-day fasting. The results of a recent phase 2 trial published earlier this year suggest that less severe energy restriction could provide bigger improvements with fewer fasting days per month. In the trial, dieters only had to restrict their calories 60% for 5 consecutive days a month over 3 months to get the benefits of the so-called "fasting-mimicking diet."
Researchers initially tested this diet in middle-aged mice, subjecting them to 4 consecutive days of the fast twice a month until their deaths. Mice on the diet lived an average of 11% longer than control mice and had fewer cancers, less inflammation, less visceral fat, slower loss of bone density, and improved cognitive performance. Autopsies revealed that fasting shrunk the rodents' kidneys, hearts, and livers, but the refeeding period appeared to kick start regeneration, increasing bone marrow-derived stem cells and progenitor cells and returning organs to normal weights. Researchers also tested the diet in a small pilot clinical trial. After 3 monthly cycles of a 5-day fasting-mimicking diet, the 19 generally healthy participants in the intervention group reported no major adverse effects and had decreased risk factors and biomarkers for aging, diabetes, cardiovascular disease, and cancer compared with the control group, which maintained its normal caloric intake. Those results were confirmed in a larger phase 2 trial reported this year, which enrolled 100 generally healthy participants.