Review
Caloric restriction: From soup to nuts

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Abstract

Caloric restriction (CR), reduced protein, methionine, or tryptophan diets; and reduced insulin and/or IGFI intracellular signaling can extend mean and/or maximum lifespan and delay deleterious age-related physiological changes in animals. Mice and flies can shift readily between the control and CR physiological states, even at older ages. Many health benefits are induced by even brief periods of CR in flies, rodents, monkeys, and humans. In humans and nonhuman primates, CR produces most of the physiologic, hematologic, hormonal, and biochemical changes it produces in other animals. In primates, CR provides protection from type 2 diabetes, cardiovascular and cerebral vascular diseases, immunological decline, malignancy, hepatotoxicity, liver fibrosis and failure, sarcopenia, inflammation, and DNA damage. It also enhances muscle mitochondrial biogenesis, affords neuroprotection; and extends mean and maximum lifespan. CR rapidly induces antineoplastic effects in mice. Most claims of lifespan extension in rodents by drugs or nutrients are confounded by CR effects. Transcription factors and co-activators involved in the regulation of mitochondrial biogenesis and energy metabolism, including SirT1, PGC-1α, AMPK and TOR may be involved in the lifespan effects of CR. Paradoxically, low body weight in middle aged and elderly humans is associated with increased mortality. Thus, enhancement of human longevity may require pharmaceutical interventions.

Introduction

Humans have been extending their average lifespans linearly since about 1840 (Oeppen and Vaupel, 2002). By 1900, the average lifespan in Europe and the USA had increased from between 22 and 35 years, to about 60 years of age. Today, the average lifespan world wide has risen to roughly 63 years (Oeppen and Vaupel, 2002). In Japan, where the longest lifespans are currently found, the life expectancy for women is almost 85 years (Oeppen and Vaupel, 2002). Because of these gains, by the 1960s, the human survival curve in developed countries began to resemble that of research animals protected in a vivarium. Because it is mostly the old who die, people born today have a better chance of reaching extreme old age than do the current “old”. For example, the life expectancy of living to 100 years for boys and girls born today in the United Kingdom is 18.1% and 23.5%, respectively (Anonymous, 2007). In contrast, a 40-year-old man and woman have only an 8% and 11.7% chance of reaching 100 years of age, respectively. As of May 26, 2008, the Los Angeles Gerontology Research Group had verified only 74 living supercentenarians (people living to 110 years of age or above) [64 females and 10 males (http://www.grg.org/Adams/Tables.htm)]. Only one human, Mme. Jeanne Calment, is credibly documented to have survived to 122 years of age.

Demographers estimate from the shape of lifespan curves in developed countries that humans are approaching the theoretical lifespan limits of our species (Olshansky et al., 2001). It has been estimated that if we successfully conquer all the diseases that currently kill us, including cancer and cardiovascular disease, that are the major killers in industrialized societies, we will extend our average lifespan by only about 15 years (Olshansky et al., 2001). Thus, even if we are lucky enough to escape all the diseases currently killing us, we will still die when we encounter the “wall” of our maximum lifespan, looming at approximately 110 years of age. Maximum lifespan is often defined as the lifespan of the longest lived 10% of a cohort. The issues surrounding our maximum lifespan are part and parcel of the health care dilemma facing the developed world. A major portion of the spending for health-related research and care by individuals, governments, private companies and foundations, doctors, hospitals, and other health care providers are focused on capturing that final 15 years of life. But, perhaps this need not be the case.

Section snippets

Lifespan effects of caloric restriction (CR)

Scientists have known since the 1930s that diets which reduce calories below the level required for maximum fertility and fecundity, while avoiding malnutrition, can extend the mean and maximum lifespan of laboratory rats, by 40% or more (McCay et al., 1935). Such dietary regimen are often termed “CR” or “dietary restriction”. Early reports also showed that CR reduces the incidence and severity of many of the diseases which limit the lifespan of rats (McCay et al., 1935). Subsequent

Conclusions

We know that it is possible to extend the mean and/or maximum lifespan of mammals by reducing dietary calories, protein, methionine, or tryptophan; or by reducing insulin and/or IGFI signaling. These interventions also delay the onset of deleterious age-related physiological changes and diseases. At least in mice and Drosophila, lifespan extension can be reversibly induced by CR, even in “middle age”. The longevity and health effects of CR are phylogenetically widespread. CR appears to be an

Acknowledgements

The author would like to thank Ms Patricia L. Mote and Ms. Mehgan Hassanzadah for reading this manuscript and providing helpful comments and suggestions.

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