Caloric Restriction

Caloric restriction is a reduction in food or energy intake while avoiding malnutrition, and it is the most potent non-pharmacological intervention to support metabolic health, with effects that exceed weight loss alone. ^[1] Reduced food intake that avoids malnutrition can ameliorate aging and aging-associated diseases in invertebrate model organisms, rodents, primates, and humans. ^[2]

Dietary restriction acts on key nutrient-sensing geroprotective signalling pathways, including AKT, FOXO, mTOR, NAD+, AMPK and FGF21, that promote healthy longevity. ^[3] Calorie restriction induces a reduction in energy expenditure larger than the loss of metabolic mass can explain, and this metabolic adaptation is theorised to reduce oxidative damage and thereby delay age-associated declines in physiological function. ^[1] Both fasting and calorie restriction upregulate autophagy across a wide variety of tissues, and because autophagy inhibition attenuates the anti-aging effects of calorie restriction, autophagy is proposed to play a substantive role in caloric-restriction-mediated longevity. ^[4]

In mice, caloric restriction increases mean lifespan from 10% to 40% compared with mice fed ad libitum and favorably affects multiple cellular pathways implicated in aging including nutrient sensing, protein synthesis, autophagy, and inflammation. ^[5] Dietary restriction also increases lifespan and protects against diabetes, cancer, and cardiovascular disease in rhesus monkeys, and in humans it causes changes that protect against these age-related pathologies. ^[6] In adults with obesity and diabetes, randomization to caloric restriction was associated with a 15% reduction in all-cause mortality and a lower incidence of weight-related chronic diseases compared with non-caloric-restriction intervention groups. ^[5] In a review of prediabetes, intensive lifestyle modification including calorie restriction and increased physical activity decreased the incidence of diabetes by 6.2 cases per 100 person-years during a 3-year period.

Therapies that inhibit aging biology, such as caloric restriction, may slow the development and progression of disease and functional decline in humans. ^[5] In persons near retirement age, an energy-restricted diet alone was less effective than diet combined with exercise and tended to decrease muscle mass, so clinicians should be aware it may contribute to sarcopenic obesity. ^[8] Maintaining a healthy weight throughout life is pivotal for healthy aging and longevity, mirroring the benefits of lifelong, moderate calorie restriction in today's obesogenic food environment. ^[9]