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. Although many hypotheses have been proposed during the past 74 years regarding the underlying mechanism, it is still not known. It is proposed that this lack of progress relates to the fact that most of these hypotheses have been based on a single underlying mechanism and that this is too narrow a focus. Rather, a broad framework is needed. Hormesis has been suggested as providing such a framework. Although it is likely that hormesis is involved in the actions of caloric restriction, it also is probably too narrowly focused. Based on currently available data, a provisional broad framework is presented depicting the complex of mechanisms that likely underlie the life-extending and other anti-aging actions of caloric restriction.

Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework.

Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.

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. The evidence for and against this possibility is considered, and it is concluded that hormesis does have an important role.

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. The conclusion is that caloric restriction underlies the life extension of rats, but not of Drosophila. Mortality characteristics show that food restriction slows the rate of aging of rats and, in some studies, of mice. However, in other mouse studies and in Drosophila, mortality characteristics have been interpreted as indicating that it delays the start but does not slow the rate of aging; the author believes that this interpretation is faulty. These differences in mortality responses to food restriction provide a potentially powerful tool for uncovering basic mechanisms underlying its life-prolonging action. A hypothesis is presented for use in the search for these mechanisms.

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. Both the findings in support of this hypothesis and those opposing it are critically considered. However, it is likely that hormesis is not the only process contributing to CR-induced life extension. It is proposed that two general processes are involved in CR-induced life extension. One is the reduced endogenous generation of damaging agents, such as reactive oxygen species. The second is hormesis, which enhances processes that protect against the action of damaging agents and also promotes processes that repair the damage once it occurs.

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). CR extends life by slowing and/or delaying the ageing processes. The underlying biological mechanism responsible for the life extension is still not known, although many hypotheses have been proposed. The Growth Retardation Hypothesis, the first proposed, has been tested and found wanting. Although there is strong evidence against the Reduction of Body Fat Hypothesis, efforts have recently been made to resurrect it. While the Reduction of Metabolic Rate Hypothesis is not supported by experimental findings, it nevertheless still has advocates. Currently, the most popular concept is the Oxidative Damage Attenuation Hypothesis; the results of several studies provide support for this hypothesis, while those of other studies do not. The Altered Glucose-Insulin System Hypothesis and the Alteration of the Growth Hormone-IGF-1 Axis Hypothesis have been gaining favor, and data have emerged that link these two hypotheses as one. Thus, it may now be more appropriate to refer to them as the Attenuation of Insulin-Like Signaling Hypothesis. Finally, the Hormesis Hypothesis may provide an overarching concept that embraces several of the other hypotheses as merely specific examples of hormetic processes. For example, the Oxidative Damage Attenuation Hypothesis probably addresses only one of likely many damaging processes that underlie aging. It is proposed that low-intensity stressors, such as CR, activate ancient hormetic defense mechanisms in organisms ranging from yeast to mammals, defending them against a variety of adversities and, when long-term, retarding senescent processes.

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. Because data on the age-related pathology and physiological functions are lacking for all of the models, except the dwarf mice, it is too early to conclude that aging is retarded in these mouse models. However, these mouse models are already providing new information about the mechanism underlying mammalian aging.

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. We report findings on terminal weight loss and food intake in male F344 rats fed ad libitum (AL group) or a life-prolonging dietary regimen in which caloric intake was restricted (DR group). Rats in both dietary groups that did not exhibit a terminal weight loss died at younger ages than those exhibiting the loss. Terminal weight loss in the AL group was not associated with decreased food intake; indeed, half of the rats in this group had an increased food intake during the period of terminal weight loss. This finding is not in accord with the presently held hypothesis. In the DR group, terminal weight loss was associated with reduced food intake. Pathology (renal disease and neoplasms) did not explain the presence or absence of the association between reduced food intake and weight loss in either dietary group. The duration of the period of terminal weight loss was similar for the AL and DR groups. Apparently, restricting calories delays the occurrence but does not affect the duration of senescent terminal weight loss.

Food restriction research: Its significance for human aging.

The total lack of knowledge concerning the nature of the primary aging processes coupled to the lack of biomarkers of aging has made it difficult to devise fruitful approaches for the study of aging. Indeed, the only index of aging about which there is general agreement is the life span of the species (i.e., the maximum age attained by members of the species). Only one manipulation has been found which extends the life span of a mammalian species and that is food restriction in rodents. In addition to increasing life span, food restriction also retards almost all age-associated physiological changes and diseases processes. It is concluded that food restriction has these diverse actions because it retards the primary aging processes. Recent research has been focused on the mechanisms by which food restriction influences the primary aging processes because it is believed that such knowledge will provide insight on the basis nature of aging. Available evidence pints to the neural an endocrine system as couplers of food restriction to the aging processes. Of particular current interest are the effects of food restriction on protein turnover and free radical metabolism. The importance of food restriction to human aging relates to the information it is expected to yield on the nature of the primary aging processes in all mammalian species and the database it should provide for interventions of human aging.