Caloric restriction.

Restricting the intake of calories has been practiced as a method for increasing both the length and quality of life for over 500 years. Experimental work confirming the success of this approach in animals has accumulated over the last 100 years. Lifelong caloric restriction (CR) may extend life by up to 50% in rodents, with progressively less impact the later in life it is started. This effect is matched by profound impacts on age related diseases including reduced risk of cancer, neurodegenerative disorders, autoimmune disease, cardiovascular disease and type II diabetes mellitus. The disposable soma theory of ageing suggests that CR evolved as a somatic protection response to enable animals to survive periods of food shortage. The shutdown of reproductive function during CR is consistent with this suggestion, but other features of the phenomenon are less consistent with this theory, and some have suggested that in rodents it may be mostly an artifact of domestication. CR induces profound effects on animals at all levels from the transcriptome to whole animal physiology and behavior. Animals under CR lose weight which is disproportionately contributed to by white adipose tissue. Generally animals on CR change their activity patterns so that they are more active prior to food delivery each day but total activity may be unchanged or reduced. Considerable debate has occurred over the effects of CR on resting metabolic rate (RMR). Total RMR declines, but as body mass and body composition also change it is unclear whether metabolism at the tissue level also declines, is unchanged or even increases. Body temperature universally decreases. Hunger is increased and does not seem to abate even with very long term restriction. Circulating adipokines are reduced reflecting the reduction in white adipose tissue (WAT) mass under restriction and there is a large reduction in circulating insulin and glucose levels. There are profound tissue level changes in metabolism with a generalized shift from carbohydrate to fat metabolism. Four pathways have been implicated in mediating the CR effect. These are the insulin like growth factor (IGF-1)/insulin signaling pathway, the sirtuin pathway, the adenosine monophosphate (AMP) activated protein kinase (AMPK) pathway and the target of rapamycin (TOR) pathway. These different pathways may interact and may all play important roles mediating different aspects of the response. Exactly how they generate the health benefits remains open for debate, however CR results in reduced oxidative stress and enhanced autophagy, both of which could be essential components of the beneficial effects. Most data about the effects of CR in mammals comes from work on rodents. There is limited work on non-human primates that shows promising effects and one randomized controlled trial in humans where physiological markers of the CR response are consistent with the responses in mice and rats. There are also populations of humans voluntarily restricting themselves. Humans on long term restriction report similar negative side effects to those observed in animals - perpetual hunger, reduced body temperature leading to a feeling of being cold, and diminished libido. Considerable effort has been directed in recent years to find drugs that mimic the CR response. Promising candidates are those that intersect with the critical signaling pathways identified above and include biguanides such as metformin that target the insulin signaling pathway, stilbenes (e.g. resveratrol) that affect sirtuin activity and drugs such as rapamycin that interact with mTOR signaling. Whether it will ever be possible to find drugs that capture the health benefits of CR without the negative side-effects remains unclear. Moreover, even if such drugs are developed how the current licensing system for drug use in western societies would cope with them may be a further obstacle to their use.