Caloric restriction-induced life extension of rats and mice: a critique of proposed mechanisms.

In 1935, Clive McCay and colleagues reported that decreasing the food intake of rats extends their life. This finding has been confirmed many times using rat and mouse models. The responsible dietary factor in rats is the reduced intake of energy; thus, this phenomenon is frequently referred to as caloric restriction.

Role of hormesis in life extension by caloric restriction.

Caloric restriction (CR) markedly extends the life of rats, mice and several other species, and it also modulates age-associated physiological deterioration and delays the occurrence and/or slows progression of age-associated diseases. The level of CR that retards the aging processes is a low-intensity stressor, which enhances the ability of rats and mice of all ages to cope with intense stressors. CR thus exhibits a hormetic action in these species, and therefore it is hypothesized that hormesis plays a role in the life-extending and anti-aging actions of CR.

The role of hormesis in life extension by dietary restriction.

The level of food restriction that results in life extension and retarded aging in rodents also enhances their ability to cope with intense stressors. Moreover, this level of dietary restriction (DR) leads to a modest increase in the daily peak concentration of plasma free corticosterone, which strongly points to DR as a low-intensity stressor. These findings suggest that hormesis plays a role in the life-extending and anti-aging actions of DR.

Dietary restriction-induced life extension: a broadly based biological phenomenon.

It is concluded that dietary restriction will extend the life of all species in the Animalia Kingdom, including the human species. This conclusion is based on the fact that hormesis is a component of the life-extending action and the other anti-aging effects of dietary restriction. It is also concluded that given the currently available database, it is not possible to predict the quantitative effect of dietary restriction on the human life span.

Caloric restriction and aging: controversial issues.

It has long been held that food restriction extends the life span of rodents and other species by decreasing caloric intake and slowing the rate of aging. Recent findings challenge these concepts. This review assesses these controversial issues.

Science fact and the SENS agenda. What can we reasonably expect from ageing research?

What can we reasonably expect from ageing research?

Overview of caloric restriction and ageing.

It has been known for some 70 years that restricting the food intake of laboratory rats extends their mean and maximum life span. In addition, such life extension has been observed over the years in many other species, including mice, hamsters, dogs, fish, invertebrate animals, and yeast. Since this life-extending action appears to be due to a restricted intake of energy, this dietary manipulation is referred to as caloric restriction (CR).

Role of sirtuin proteins in life extension by caloric restriction.

The deacetylase activity of sirtuin proteins may play a key role in the life extending action of caloric restriction in organisms ranging from yeast to mammals. Recent research has been focused on the possible afferent pathway by which caloric restriction increases the deacetylase activity and on the efferent pathway by which the increased deacetylase activity extends life. Further research is needed to firmly establish the role of sirtuin proteins in life extension by caloric restriction in mammals.

Genetic mouse models of extended lifespan.

Since 1996, seven genetic mouse models have been reported to show increased lifespan: Ames and Snell dwarf mice, the 'little mouse' (Ghrhr(lit/lit)), mice null for either growth hormone receptor/binding protein (GHR/BP(-/-)) or p66(shc) (p66(shc-/-)), mice heterozygous for the IGF-I receptor (Igf1r(+/-)), and fat-specific insulin receptor knockout mice. In this article, we describe and evaluate these mouse models with respect to their relevance for aging studies. While these seven genetic models all show a significant increase in lifespan, issues of sample size and animal husbandry procedures require further evaluation before firm conclusions can be drawn on the reproducibility of life extension in most of these mouse models.

Subfield history: caloric restriction, slowing aging, and extending life.

Caloric restriction has resulted in a consistent robust increase in the maximal length of life in mammalian species. This article reviews significant advances over the long history of research on calorie restriction and longevity.

Senescent terminal weight loss in the male F344 rat.

Loss of weight, often of unknown cause and culminating in death, commonly occurs in humans at advanced ages. Rats that live to old ages, such as the Fischer 344 (F344) strain, also exhibit a terminal loss in body weight. A presently held hypothesis is that the terminal weight loss in the F344 rat model is due to reduced food intake because of an alteration in hypothalamic function resulting in early satiation.

Physiology of aging.

Although physiological deterioration occurs with advancing adult age, the interpretation of cross-sectional and longitudinal studies of age-changes in physiological processes are often complicated by confounders unrelated to aging. Age-associated disease is a major cause of physiological deterioration. To avoid this factor, only subjects free of discernible disease are used in many studies of what is referred to as "normal" aging.

Caloric restriction and aging: an update.

Restricting food intake to 50 to 70% of that eaten by ad lib-fed rats and mice markedly increases longevity, retards age-associated physiological deterioration, and delays and, in some cases, prevents age-associated diseases. These actions are due to the reduced intake of calories, and thus the phenomenon has been called the antiaging action of caloric restriction (CR). This article focuses on the possible biological mechanisms underlying the antiaging action.

Influence of caloric intake on aging and on the response to stressors.

Reducing the food intake of rodents to well below that of ad libitum fed animals increases the life span. This action, which gerontologists often refer to as the antiaging action of dietary restriction (DR), is due to the slowing of the aging processes. DR also maintains most physiological processes in a youthful state and delays the occurrence and/or slows the progression of age-associated disease processes.

Hormesis and the antiaging action of dietary restriction.

Hormesis refers to the often encountered phenomenon of a beneficial biological action from a factor or agent that is generally viewed as detrimental. Beneficial actions that have been observed include life span extension. It is proposed that life span extension in rodents by dietary restriction is an example of hormesis and that sustained moderate hyperadrenocorticism underlies this life prolongation.

Possible mechanisms underlying the antiaging actions of caloric restriction.

Restricting the food intake of mice and rats to well below that of ad libitum-fed animals markedly slows the aging processes. This action is reflected in an increase in longevity, a decrease in the age-associated increase in age-specific mortality rate, the maintenance of the physiological processes in a youthful state even at advanced ages, and the delaying of the onset or slowing of the progression or both of most age-associated diseases. The dietary factor responsible is the reduction in energy (caloric) intake.