Caloric restriction is the practice of long-term reduced dietary intake, typically characterized by a 20 to 50 percent decrease in caloric intake below habitual levels, without malnutrition or deprivation of essential nutrients. It involves a consistent pattern of reducing average daily caloric intake and differs from fasting and other restrictive eating patterns in that the latter regimens primarily focus on the frequency and timing of eating rather than a pattern of permanent, long-term restriction.

Caloric restriction in animals

Caloric restriction delays the onset of age-related chronic diseases in various species, including yeast, worms, flies, fish, mice, rats, and monkeys. It is the only known non-genetic method demonstrating the capacity to prolong lifespan in multiple organisms. Scientists first posited caloric restriction as a dietary intervention to extend lifespan more than 80 years ago based on findings from a study in which rats fed a healthy, low-calorie diet outlived rats that were allowed to feed freely.^[1]

Two long-term studies conducted at the University of Wisconsin (UW) and the National Institute of Aging (NIA) investigated caloric restriction's health and longevity effects in rhesus monkeys.^[2][3][4][5] The two studies yielded different, and sometimes conflicting, results. For example, both studies demonstrated that calorie restriction was associated with a two-fold decrease in the risk of developing age-related diseases compared to control monkeys. In addition, monkeys from both studies exhibited improvements in blood glucose control. On the other hand, survivability rates differed between the two studies. Death rates among control monkeys in the UW study were nearly twice that of the calorie-restricted monkeys. However, the NIA study showed no benefits regarding the monkeys' survivability.

There were notable differences in the two studies' designs. For example, the monkeys differed in terms of their ages and places of origin. Monkeys from different places of origin are often genetically different. The two diets differed as well. The monkeys at UW ate a standardized diet (chow), but the monkeys at NIA ate a natural diet subject to seasonal variation. The two diets were similar in caloric content (30 percent restriction) but differed in overall nutrient and fiber content. The UW diet was considerably higher in sugar (sucrose) than the NIA diet. In addition, the feeding schedules on which the monkeys ate differed, with the UW monkeys allowed to eat freely during the day but deprived of food overnight and the NIA monkeys restricted during the day but allowed to eat overnight.

Rhesus monkeys share many genetic and physiological characteristics with humans and are good models for studying aging and disease in humans. Despite the critical differences in the findings from these studies, substantial evidence suggests that caloric restriction may serve as a means to increase human healthspan.

People with Huntington's disease frequently have hyperglycemia and tend to develop diabetes at much higher rates than unaffected relatives.^[6] Mice in experimental models of Huntington's disease exhibit these features as well. When placed on an every-other-day fast, mice genetically engineered to develop Huntington's disease experienced a 10 percent delay in the onset of neurological symptoms and lived 10 percent longer than those allowed to eat at will. They also exhibited significantly fewer signs of brain atrophy (thinning of the cerebral cortex and expansion of the ventricular areas beneath) and had fewer huntingtin protein aggregates in the brain.^[7]

Caloric restriction in humans

In short-term human studies of caloric restriction in humans, participants' resting metabolic rates decreased over time, with reductions of ~100 kcal per day after just three weeks of 20 percent caloric restriction and ~255 kcal per day after ten weeks.^[8][9] Participants in the longer, 10-week study also experienced reduced systolic and diastolic blood pressures, improved fibrinolysis (a normal process involved in the destruction of blood clots), and lower blood glucose levels.

Long-term calorie restriction induces global biochemical and molecular changes in humans. Researchers evaluated the effects of these changes in a study involving 37 men and women who practiced voluntary long-term caloric restriction (approximately 30 percent of habitual intake) for 3 to 15 years, compared to sedentary and fit people eating a traditional Western diet. The participants who practiced long-term caloric restriction exhibited increased cortisol levels and decreased inflammation compared to those who ate the Western diet. In addition, factors involved in cellular housekeeping activities (such as autophagy) increased in the calorie-restricted group.^[10]

Three multicenter pilot studies of caloric restriction have investigated the feasibility and outcomes of long-term calorie restriction in humans. The pilot studies, called CALERIE 1 (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy), involved healthy, non-obese people who practiced 20 to 30 percent caloric restriction for six or 12 months. Each of the studies employed different modalities, and the participants' ages, pre-study body weights, and levels of caloric restriction varied considerably. However, the investigators noted a few generalizations regarding the outcomes. The participants' energy expenditure, core body temperature, fasting insulin levels, bone mass, muscle size and strength, and markers of oxidative stress and DNA damage decreased. Conversely, their insulin sensitivity, mitochondrial DNA synthesis, and mitochondrial mass increased. However, some pilot studies observed improved lipid profiles, but not all.^[11]

CALERIE 2, a long-term (two-year) study involving 218 young and middle-aged, normal-weight, or moderately overweight adults randomized to follow either a 25 percent calorie-restricted diet for two years or their usual diet, found that participants whose diet was restricted exhibited lower total cholesterol, LDL-cholesterol, triglycerides, C-reactive protein, TNF-alpha, and blood pressure at the end of the study period. In addition, their HDL-cholesterol and insulin sensitivity increased. However, none of the study participants achieved the full 25 percent restriction, averaging 12 percent restriction over two years.^[11]

"Those who attempted a 25% calorie-restricted diet for two years resulted in lower total cholesterol, LDL-cholesterol, triglycerides, C-reactive protein, TNF-alpha, and blood pressure even though they only were able to achieve 12% calorie-restriction." Click To Tweet

Mechanisms associated with caloric restriction

Scientists don't fully understand the mechanisms by which caloric restriction works. However, they appear to involve inhibiting key nutrient-sensing and inflammatory pathways and regulating multiple molecular, cellular, and metabolic pathways that promote protein homeostasis, genomic stability, oxidative stress resistance, and proper stem cell function. Some of the molecular adaptations identified involve increased activity of sirtuins, FOXO proteins, AMPK, and Nrf2, while cellular adaptations include increased autophagy, DNA repair, and immunosurveillance, among others. These adaptations promote metabolic improvements via decreased IGF-1, mTOR, insulin, inflammation, and oxidative stress.^[12]

Learn more about FOXO proteins in this overview article.

Learn more about sirtuins in this overview article.

Learn more about autophagy in this overview article.

Challenges of caloric restriction

Notably, most of the relevant studies on caloric restriction have been conducted in a laboratory setting using various animal models, from yeast cells to monkeys. Extrapolating the findings from these studies to humans presents challenges. In particular, most of the clinical trials of caloric restriction have lasted only a few weeks or months – insufficient time to induce the metabolic and hormonal adaptations associated with caloric restriction and believed to increase lifespan in lower organisms and rodents. Since some of the study participants in these trials were obese, teasing out the benefits of caloric restriction from those that invariably accompany the weight loss associated with the practice is difficult.

In addition, caloric restriction is difficult to adhere to. In some animal studies, the animals receive meager quantities of food – sometimes as much as 50 percent of normal intake. In human trials of voluntary caloric restriction, however, participants rarely achieve the desired level of restriction and most gradually increase their intake over time.^[11] Furthermore, people who follow a calorie-restricted diet tend to gravitate toward higher protein foods, which provide greater satiety. Protein intake activates signaling pathways such as those involving mTOR and IGF-1, undermining some of the beneficial effects of caloric restriction observed in lower organisms.^[13]

Alternatives to caloric restriction

Some evidence suggests that other forms of restrictive eating practices may offer the same (or greater) benefits associated with caloric restriction but are more sustainable. In the absence of ready supplies of glucose and fats from meals, restrictive eating practices induce a cellular "energy crisis." This crisis, in turn, liberates fat stores via fatty acid oxidation and ketone production while prioritizing safeguarding lean muscle mass and function. Restrictive eating practices drive mechanisms that improve overall body composition and trigger the activation of biochemical processes and signaling pathways that optimize human performance and physiological function, possibly slowing the processes of aging and disease. These eating practices include:

• Time-restricted eating – limiting food intake to certain hours of the day without overtly reducing caloric intake.
• Alternate-day fasting – abstaining from food and non-water beverages every other day while eating normally on non-fasting days.
• Prolonged fasting (multi-day, sometimes referred to as periodic fasting) – fasting for more than 48 hours.

Learn more about time-restricted eating in this overview article.

Learn more about fasting in this overview article.

Conclusion

Caloric restriction delays the onset of age-related chronic diseases and prolongs lifespan in multiple organisms. Clinical trials suggest that caloric restriction may offer similar health benefits to humans, but the studies have been too short to provide conclusive results. In addition, the practice of caloric restriction is not sustainable for most people, but other (more sustainable) dietary interventions may provide similar, if not greater, health effects.