The practice of calorie restriction reliably slows aging and extends life span in most species tested to date. The degree to which this happens is much reduced in longer-lived species, but a detailed understanding of why this is the case is yet to be assembled. It makes sense from an evolutionary perspective: extended health and life in response to famine helps to raise the odds of successful reproduction. Famines tend to be seasonal, and a season is a large fraction of a mouse life span, but only a tiny faction of a human life span. Thus only short-lived species evolve a sizable gain in life span in response to reduced calorie intake, even though the short-term benefits to health appear quite similar in both short-lived and long-lived mammals.
From a biochemical perspective, cellular metabolism is so complex, and calorie restriction changes so much of it, that it remains a major undertaking to try to put everything in order to understand how exactly calorie restriction works. It is clearly an adaptive response, a shift of the whole of metabolism from one state into another, a change of great complexity. Deciphering all of the details is a fascinating scientific endeavor, but one that will come to be of increasingly little relevance to the future of human longevity. Calorie restriction mimetic therapies that modestly slow aging are hard to construct, while rejuvenation therapies based on repair of the damage that causes aging will deliver far greater benefits with far lower expense.
In 1989, the anti-aging and prolongevity actions of calorie restriction (CR) were explained from the evolutionary viewpoint of organisms having evolved adaptive response systems to maximize survival during periods of food shortage. On the basis of this evolutionary viewpoint, we divided the beneficial actions of CR into two systems; "systems activated under sufficient energy resource conditions" and "systems activated under insufficient energy resource conditions". The former is activated under natural environmental conditions that grant animals free use of energy by providing a plentiful food supply. In other words, when there is grace for free use of energy, animals grow well, reproduce more, and store excess energy as triglyceride in white adipose tissue for later use, but not to such an extent that they become obese. The latter is activated under natural environmental conditions that do not permit free use of energy because of food shortages.
In other words, when there is no grace for free use of energy, animals suppress growth and reproduction and shift energy use from growth and reproduction to maintenance of biological function, but not to such an extent that they become severely starved. Adaptation to natural environmental changes is a top priority for survival in animals. On the basis of the adaptive response hypothesis, we propose a suite of mechanisms for the beneficial actions of CR. Since experimental CR conditions can mimic insufficient energy conditions, we hypothesized that CR suppresses "systems activated under sufficient energy conditions" and activates "systems activated under insufficient energy conditions", and additively induces anti-aging and prolongevity actions. The first set of systems involves GH/IGF1, FOXO, mTOR, adiponectin and BMAL1 signaling, and CR appears to suppress these anabolic reactions. The second set of systems involves SREBP-1c/mitochondria redox, SIRT and NPY signaling, and it is likely that CR activates these reactions to make optimal use of insufficient energy resources.
Studies using monkeys suggest that the beneficial actions of CR may occur in humans as well as other mammals. Ongoing CR research focuses on two themes, i.e. elucidation of the molecular mechanisms of CR, and development of CR mimetic medicines. We consider development of novel CR mimetic medicines to be difficult without an understanding of the molecular mechanisms of CR. To develop CR mimetic medicines that are applicable to humans, further studies are therefore required on the molecular mechanisms of CR, particularly in non-human primates. In this report, we propose that the molecular mechanisms of beneficial actions of CR should be classified and discussed according to whether they operate under rich or insufficient energy resource conditions. Future studies of the molecular mechanisms of the beneficial actions of CR should also consider the extent to which the signals/factors involved contribute to the anti-oxidative, anti-inflammatory, anti-tumor and other CR actions in each tissue or organ, and thereby lead to anti-aging and prolongevity.