Isao Shimokawa, MD, PhD
Pathology & Gerontology,
Department of Respiratory and Digestive Medicine,
Nagasaki University School of Medicine,
Nagasaki, Japan.

Introduction
Caloric restriction (CR)--the restriction of food intake while maintaining adequate supplies of essential nutrients (i.e. not malnutrition)--is widely recognized as the most powerful intervention for the extension of lifespan in organisms. CR slows the aging process, prevents or retards age-related diseases and extends the mean and maximum lifespan in laboratory organisms.^1,2 In the 66 years since the seminal report of McCay,³ many studies have confirmed its life-extending effects. These effects do not depend on the restriction of specific nutrients or food contaminants.4 Despite numerous efforts, our knowledge of the mechanisms underlying the effects of CR is not yet complete. The present article focuses on several possible mechanisms. Other historic and recent research can be found in more comprehensive reviews^1,2 and a recent update.⁴

An Evolutionary Perspective
It has been suggested that the anti-aging effects of CR might derive from adaptive responses that evolved to maximize organism survival during periods of food shortage. In order to avoid extinction, organisms have evolved neuroendocrine and metabolic response systems to enhance survival during natural periods of food shortage.

Caloric Restriction Leads to Extended Life Span

Recently, the World Health Organization published a Longevity Report Card for the world's nations. This latest report card now rates different countries according to the number of years their average citizen can expect to live "disease-free". Although this new measure is still based on statistical assumptions, it provides an additional index to measure the effectiveness of national healthcare systems in extending 'good' health. Canada ranked 12th on the basis of this new measure, a number of notches below its 7th place in the total life expectancy ratings.

The new WHO index does not mean that the average life span (the average length of human life defined in terms of calendar years) has changed in Canada or anywhere else. Better nutrition, public sanitation, vaccination, and antibiotics have increased the average life expectancy, (one's statistical likelihood of living to a certain age), but so far these advances have failed to raise the ceiling on the maximum human life span

What, you might ask, can be done to raise this ceiling? Even more importantly, if we are to take the WHO statistics seriously, what can save the average 72-year-old Canadian from the rapid onset of diseases?

The answer may be startlingly simple: greatly restrict your consumption of calories! Under-nutrition, as opposed to malnutrition, may be the key to slowing down aging. In the recent Scientific American Supplement on Aging, a fascinating article, "The Famine of Youth," discusses overwhelming evidence in support of caloric restriction. As one writer in the Scientific American states, caloric restriction has "proven to increase life span in virtually every species in which it has been tested, from parameciums and worms to spiders, and rodents". This caloric restriction worked even when it was initiated in adult specimens. Not only do they live longer--the onset of most idiopathic diseases of old age in these creatures is delayed. Caloric restriction seems to have a "profound inhibitory effect on tumours," and, moreover, it "delay(s) the age-related deterioration in every major physiological system."

A recent study using gene chips showed that caloric restriction reduced the age-related increase in stress proteins, which are proteins required for the repair or elimination of damaged DNA and proteins. In this issue, we have interviewed Dr. Tomas Prolla (see page 36), who has been working with Dr. Richard Weinduch, at the University of Wisconsin, both of whom are in the forefront of research into the biology of aging. Their studies provided the first cellular markers for aging, a long-desired objective of aging research; they have also shown that caloric restriction retards the expression of these markers. Dr. Weinduch and Dr. Prolla are currently organizing a large study involving 200 monkeys [coordinated in conjunction with the National Institute on Aging (NIA)] to test whether caloric restriction extends life-span in higher primates. Unfortunately, it will be another twenty years or more before we will know whether the life-span in these monkeys has indeed increased. However, all findings to date demonstrate that the early responses to caloric restriction in these animals are comparable to responses in other species, in which the life-span has been significantly increased.

A few short caloric restriction studies have been carried out in humans. It was found that reducing food consumption to approximately 1800 calories per day, for at least six months, resulted not only in a 10-15% reduction in body weight, but also in a 20% drop in blood pressure, a 35% drop in cholesterol levels, and a 31% drop in serum lipid levels. These changes parallel those changes observed in calorically restricted animals.

While it is important to discover whether caloric restriction affects our health and longevity, the significance of this is, of course, not to impose a dietary "famine" on people, but to understand the physiological and genetic mechanisms triggered by caloric restriction. How does it extend life and retard the onset of disease? The goal of this research is to find alternative means of affecting the same mechanisms, in order to fool our cells into thinking that they are being deprived of calories. This would be tantamount to a fountain of youth pill. Dr. Prolla's group is already experimenting with dietary supplements, vitamins, nutraceuticals, and certain drugs to determine their anti-aging effects on various tissues.

Sources

1. Clark,W.R. 1999. A Means to an End. The biological basis of aging and death. Oxford University Press, Oxford.
2. Scientific American Presents. Summer 2000 volume II Number 2.