A great deal of present day research is in one way or another focused on forms of lowered calorie intake. There are those who seek to fully map the mechanisms by which calorie restriction and intermittent fasting improve health and extend life significantly in short lived species. There are those who are trying to sufficiently quantify the benefits to be able to produce robust calorie-specific medical diets. There are those who are trying to find pharmaceuticals that partially replicate the changes induced by nutrient sensing regulators of metabolism, and thus improve health without eating less.
Any investigation of the mechanisms of calorie restriction and intermittent fasting is a complex business: a lower calorie intake produces sweeping changes in the behavior of cells and systems in the body, and metabolism is far from completely understood. The research community will only understand the fine details of exactly how eating less increases life span when they understand the fine details of cellular metabolism as a whole: how variations in metabolism determines variations in pace of aging. The achievement of that challenging goal lies decades in the future, which is one good reason not to bet on calorie restriction and fasting mimetic drugs to produce large gains in human life span any time soon.
The worldwide increase in life expectancy has not been paralleled by an equivalent increase in healthy aging. Developed and developing countries are facing social and economic challenges caused by disproportional increases in their elderly populations and the accompanying burden of chronic diseases. The primary goal of aging research is to improve the health of older persons and to design and test interventions that may prevent or delay age-related diseases. Although environmental quality and genetics are not under our direct control, energy intake is. Both hypo- and hypernutrition have the potential to increase the risk of chronic disease and premature death. Manipulation of a nutritionally balanced diet, whether by altering caloric intake or meal timing, can lead to a delay of the onset and progression of diseases and to a healthier and longer life in most organisms.
An emerging area of research is the investigation of the independent consequences of variations in meal size (through the control of energy intake) and meal frequency (by controlling the time of feeding and fasting) on the incidence or amelioration of multiple age-related diseases, including cardiovascular disease, diabetes, cancer, and dementia. These studies are starting to reveal that health-span and life-span extension can be achieved by interventions that do not require an overall reduction in caloric intake.
We discuss four experimental strategies aimed at altering energy intake or the duration of fasting and feeding periods that result in improved aspects of health in mammals. These are (i) classical caloric restriction, in which daily caloric intake is typically decreased by 15 to 40%; (ii) time-restricted feeding (TRF), which limits daily intake of food to a 4- to 12-hour window; (iii) intermittent or periodic full or partial fasting, that is a periodic, full- or multiday decrease in food intake; and (iv) fasting-mimicking diets (FMDs) that use a strategy to maintain a physiological fasting-like state by reducing caloric intake and modifying diet composition but not necessarily fasting. We also summarize the metabolic and cellular responses triggered by these feeding regimens and their impact on physiology, focusing on studies in rodents, monkeys, and humans.
Although the specific mechanisms are far from being fully understood, this periodic absence of energy intake appears to improve multiple risk factors and, in some cases, reverse disease progression in mice and humans. Thus, the time is ripe to add to our understanding of the molecular mechanisms of action and efficacy of these dietary interventions to the foundation for future clinical trials. We expect that these dietary interventions combined with classical pharmacology and clinical practice will yield interventions that will improve human health and enhance health span and quality of life as we grow old.