This open access review paper comes from scientists long involved in calorie restriction research, in search of mechanisms to explain why a lower calorie intake results in improved health and life span, and attempting to quantify the benefits in humans:
The discovery that aging can be ameliorated by dietary, genetic, and pharmacological interventions has opened up the prospect of a broad-spectrum, preventive medicine for aging-related diseases. Single-gene mutations that extend animal lifespan can ameliorate natural, age-dependent loss of function and the pathology of aging-related diseases, including neurodegeneration. Furthermore, laboratory animal models of slowed aging, naturally long-lived species such as the naked mole rat, and some humans that achieve the age of 100 have all demonstrated that a long life is not inevitably associated with late-life disability and disease. Recent work has shown that specific dietary interventions can also promote long life and healthy old age.
Reduced food intake, avoiding malnutrition, can ameliorate aging and aging-associated diseases in invertebrate model organisms, rodents, primates, and humans. Dietary restriction (DR), implemented as chronic and coordinate reduced intake of all dietary constituents except vitamins and minerals, was first shown 80 years ago to extend lifespan in rats. DR in both rats and mice improves most aspects of health during aging. Exceptions include resistance to infection and wound healing. However, these conditions rapidly improve with re-feeding, and DR animals can then outperform controls. DR can produce substantial benefits with, for instance, ∼30% of DR animals dying at old ages without gross pathological lesions, compared with only 6% of ad-libitum-fed controls. DR started in young, adult Rhesus monkeys greatly improves metabolic health; prevents obesity; delays the onset of sarcopenia, presbycusis, and brain atrophy; and reduces the risk of developing and dying of type 2 diabetes, cancer, and cardiovascular disease.
Recent findings indicate that meal timing is crucial, with both intermittent fasting and adjusted diurnal rhythm of feeding improving health and function, in the absence of changes in overall intake. Lowered intake of particular nutrients rather than of overall calories is also key, with protein and specific amino acids playing prominent roles. Nutritional modulation of the microbiome can also be important, and there are long-term, including inter-generational, effects of diet. The metabolic, molecular, and cellular mechanisms that mediate both improvement in health during aging to diet and genetic variation in the response to diet are being identified. These new findings are opening the way to specific dietary and pharmacological interventions to recapture the full potential benefits of dietary restriction, which humans can find difficult to maintain voluntarily.