Reduced energy intake: the secret to a long and healthy life?

The effect of energy consumption on health-span and life-span

Throughout history, numerous societies have recognized the beneficial effects on health and general wellbeing of limiting food intake for certain periods of time, either for religious beliefs or when food was scarce. More than 70 years ago, the first controlled scientific study of energy restricted diets and their ability to extend life-span was published by McCay and colleagues [38]. McCay showed that feeding rats with a diet containing indigestible cellulose significantly extended both the mean and maximum lifespan of these rats. Since then, numerous other studies have confirmed this observation and the results have been extended to many other species, including mice [54, 49], fruitflies [8], nematodes [21], water fleas, spiders and fish [54]. Variations of this basic dietary regime are the most effective way of extending life-span of mammals without genetically altering them. Reductions in energy intake of 25–40% below the ad libitum energy intake level, are known to increase both the mean and maximum life-span of rats and mice by 25–40%. Maximum extension of life-span (and health-span) has been shown to be achieved when CR is initiated in young, post-pubertal, animals. The amount by which CR extends life-span in rodents depends upon the baseline energy intake of the control ad libitum fed animals and on the magnitude of the CR. Life-span extension in mammals has been shown to increase progressively as caloric intake is reduced, until the point of starvation.

Rodents maintained on reduced energy diets are generally smaller and leaner and they have less body fat and smaller major organs than ad libitum fed animals [53]. Animals on CR diets are generally more active, which may relate to the need to search for food [20, 34] and the normal age-related decline in physical activity is markedly reduced in CR animals [39]. See Figure 1 for an overview of some of the effects of CR on laboratory animals.

Potential molecular mechanisms of caloric restriction

The acquisition of food and energy sources is one of the most important and vital behavioral traits and therefore the removal or limitation of food and energy sources will cause a certain degree of physiological and emotional stress in the organism. The exact mechanisms whereby a dietary regime of reduced caloric intake can increase both health-and life-span are presently still unclear. A vast array of potential mechanisms are thought to be involved in the beneficial actions of CR and these include: alteration in stress responses (i.e. CR can induce a mild stress response, presumably due to reduced glucose availability, which protects cells from oxidative stress and excitotoxic insults), increased formation of ketone bodies, alterations in glucose and insulin signalling, alterations in cytokine signalling and immune function, alterations in satiety and adipose-generated hormones, sirtuin signalling, peroxisome proliferators-activated receptor (PPAR) signalling, and FoxO transcription factor activation and signalling [for review see 33].

Adverse effects of caloric restriction

Although CR can increase life-span and reduce the incidence of many major diseases, several adverse consequences of CR have been reported. Wound healing is impaired in rats maintained on a CR diet, which is associated with decreased collagen production by skin cells [44]. Some aspects of immune function may also be compromised by CR. For example, the ability of deer mice to generate an immune response on re-exposure to an antigen (immunological memory) was impaired when they were maintained on a CR diet [35]. In another study it was shown that CR increases the mortality of old mice caused by exposure to influenza virus [16].

Thus, while CR improves the function and longevity of most tissues and organs, there are some exceptions. Interestingly, even different subpopulations of cells within a tissue can be differentially affected by CR. For example, many types of neurons within the brain are positively affected by CR in ways that may increase their resistance to Alzheimer’s, Parkinson’s and Huntington’s disease [33]. However, motor neurons in the spinal cord may be adversely affected by CR in ways that increase their vulnerability to amyotrophic lateral sclerosis [37]. Finally, there is considerable evidence that CR can impact negatively on reproductive and neuroendocrine systems of females. Thus, females subjected to CR can develop amenorrhea and may greatly increase their spontaneous exercise resulting in anorexia nervosa [14, 34]. A better understanding of how the magnitude of CR, including meal size and frequency, impact on specific cell types and organ systems will be necessary to develop specific CR regimes that are tailored for individuals depending upon their age, sex and activity level.

Caloric restriction in humans – Would it work and is it feasible?

In humans, overeating promotes disease in multiple organs systems (for example, type 2 diabetes and cardiovascular disease) and is known to shorten both life-span and health-span. In the United States, overeating and obesity is now considered a leading cause of morbidity and mortality [3, 5]. Obesity is a public health and policy problem because of its prevalence, costs and burdens and the prevalence of obesity has been continually rising throughout the world. Caloric restriction reduces disease risk in overweight individuals and could potentially also have beneficial effects in individuals with a normal, healthy bodyweight. Presently, it seems unlikely that we will ever establish with certainty whether CR increases maximum life-span in humans. Additionally, the form of CR that might work best in humans is also unknown and perhaps short-term fasts might be easier than the continuous daily grind of CR. Multiple studies are underway to determine whether CR would be beneficial in primates. There are currently two major studies of CR in Rhesus monkeys (non-human primates) in progress, one at the University of Wisconsin at Madison and the other at the National Institute on Aging’s Intramural Research Program that could, within the next 15–20 years, determine whether CR indeed increases maximum life-span in non-human primates. Data collected from these two important studies have shown that CR offers protection against the development of insulin resistance and type 2 diabetes, reduces the risk of developing atherosclerosis and cardiovascular disease, reduces circulating levels of triidothyronine, lowers metabolic rate and core body temperature, reduces oxidative stress and damage, lowers circulating levels of IGF-1 and IL6, and improves overall immune function [40, 28, 29, 57].

One caveat that needs to be taken into account when examining data from CR studies is that the majority of energy restricted animals are compared to ad libitum fed animals. Laboratory rats and mice that are fed ad libitum amounts of standard rodent food tend to overeat and become overweight or obese. Additionally laboratory animals experience a lack of both mental and physical activity. Hence, it is not entirely surprising that an animal that has a lower body weight and exerts more physical and mental activity (as animals will attempt to search for food in their home cage) has a longer health- and lifespan than an overweight ad libitum fed laboratory animal. It still remains unclear whether reducing energy intake in an animal that already has a healthy bodyweight and sufficient amounts of physical and mental activity will increase its health- and maximum life-span. This remains an important issue to be addressed by the current CR research community.

Another factor to consider with the direct translation of a CR dietary regime from laboratory rodents to humans is compliance. Adhering to a CR dietary regime, such as a 20% or 40% decrease in overall caloric intake, would require major dietary and lifestyle changes. These changes might not be practical in the high-stress, fast-paced environment that we live in today. Considering that the incidence of obesity is rapidly increasing in both industrialized and developing nations, it remains to be seen whether many people would be able to comply with such a strict dietary regime as 20% or 40% CR. Perhaps by encouraging healthy eating and physical and mental activity by providing wide-spread access to healthy eating education programs, low-cost and readily available healthy and nutritious food, and sufficient time for daily physical activity and exercise, we could potentially increase health-span and reduce the risk of diseases, such as type 2 diabetes, dietary related cancers and cardiovascular disease, significantly more so in a larger number of people than any strict caloric restriction or energy restriction dietary regime would be able to do.