FEATURE ARTICLE
Aging: A Biological Perspective
A variety of techniques extend the lives of model organisms, and similar approaches might help human beings stay healthy longer
Robert Arking
Cutting Back the Calories
In 1934, Clive McCay and Mary Crowell of Cornell delayed the onset of senescence in rats by reducing how much they ate. In fact, reducing the calories in an animal's diet by about 40 percent, while keeping the different nutrients at normal levels, results in healthy and long-lived mice and rats. It also works for flies and worms. In fact, hundreds of studies show that caloric restriction lengthens life. Similar experiments are underway in macaque monkeys, and, although these long-term experiments are still in progress, the available data suggest that caloric restriction may lengthen primate lives, too. There is good evidence, put forth by Mark Lane and his colleagues at the National Institute on Aging, suggesting that caloric restriction utilizes a hormonal mechanism to exert its effects on all the different tissues of the body.
Caloric restriction creates measurable changes in a variety of biomarkers. For example, George Roth and his colleagues at the National Institute on Aging put male rhesus monkeys on a 30-percent reduction in calories for three to five years. When compared with control monkeys, the ones on reduced calories displayed significantly lower body temperature, reduced plasma levels of insulin and increased serum levels of dehydroepiandrosterone sulfate, a steroid hormone precursor molecule that commonly decreases in aging monkeys and humans. We do not yet known if these monkeys will in fact live long, but it is interesting to note that these same three traits were found in long-lived human males.
Scientists can also correlate gene-expression patterns with differential mortality for adults of different ages or who received different treatments. This maps physiological function and mortality on the expression states of the genome, which can be determined with DNA chips, or microarrays (see Figure 5). In essence, a matrix of hundreds or thousands of oligonucleotides arranged in a matrix on a slide makes up a DNA chip. Messenger RNA (mRNA) newly transcribed from the genes in an experimental sample or a control can be labeled with fluorescent tags and each then applied to its own chip. If a section of nucleotides on a piece of mRNA being tested complements one of the attached oligonucleotide probes, then the two pieces of chromosomal material hybridize. Non-hybridized material is washed off. Finally, a scanner measures the level of fluorescence at each spot on the matrix, so that the expression of the experimental and control samples can be compared.
These microarrays can distinguish between gene-expression patterns of healthy and sick animals or young and old ones. Such microarrays can even differentiate between normal-lived and long-lived animals, despite the difficult statistical problems inherent in the technique. My comparison of several independent experiments leads to the reasonable assumption that each tissue has its own characteristic aging pattern. Skeletal muscle and heart muscle, for example, are very similar to each other, but they age in very different manners. Although both of these are different than neural tissue, certain broad functional similarities exist. All tissues show an increased stress response, likely coupled to increased levels of highly reactive molecules called reactive oxygen species (ROS), or less accurately free radicals, and to an increased level of cellular damage. Aging tissues also seem less capable of processing signal proteins or synthesizing and degrading other proteins. Both of these processes—increased ROS production and decreased signal sensitivity/protein turnover—might set off positive feedback cycles that progressively degrade an aging cell's performance in these and other areas.
Caloric restriction, on the other hand, brings about a variety of changes that seem to have the effect of maintaining the optimal function of the tissue by reducing the stress levels within the cell while retaining the optimal metabolic, biosynthetic and turnover capabilities of the cells. As a result, the animals shift their focus from growth and reproduction to somatic repair and maintenance. The restricted animals age more slowly and maintain their tissue integrity well into old age. They also show either a significant delay or a complete elimination of the onset of many age-related pathologies, and their survival curves are characterized by a significant extension of the health span. In addition to aging more slowly, calorically restricted animals stay physically healthier and mentally active much longer then normally fed controls. On the other hand, calorically restricted animals grow more slowly than normal, are often less fecund and are sometimes less resistant to environmental stresses.
Although reducing calories makes lab animals live longer, it hardly promises a reasonable approach for humans. Even if promised extended longevity, few people would willingly cut back on calories by 40 percent.
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