Caloric Restriction and Aging Scientific American Jan 96

This article outlines the evidence for caloric restirction and slowed aging and suggests a human dietary regime consistent with the research. The diet is quite sustainable but might feel somewhat lean as the monkey regime causes precipitous falls in insulin level , results in significant loss of weight and a two degree fall in body temperature. There are also other ways of prolonging life through constructive diet such as the intake of anti-oxidant vitamins and bioflavinoids which reduce free radicals.

There are several explanations for this. The Scientific American article cites free-radical damage to the mitochondria but there are also specific gene activation responses common to worms and rodents which may be important and evidence also about immune proteins and cancer these are discussed in the following New Scientist articles.

In rodents dietary restriction postpones age-related declines in blood glucose control, female reproductive capacity, DNA repair, immunity, learning ability, muscle mass, and protein synthesis. It slows age-related increases in cross-linking of long-lived protiens, free-radical production by mitochondria, unrepaired oxidative damage to tissues, and delays onset of auto-immune disorders, cancers, cataracts, diabetes, hypertension and kidney failure.

Rhesus Monkeys: Normal Diet Reduced


New Scientist 97

A NEW genetic switch that prolongs life has come to light, say scientists studying the worm Caenorhabditis elegans. They believe that when food is scarce, levels of an insulin-like hormone in the worm's body drop, activating its longevity programma. Previous studies showedthat various mutations allow nematodes to live far longer than usual (New Scientist, Science, 25 May 1996, p 16 see below for graph). Now groups led by Cynthia Kenyon of the University of Califomia at San Francisco and Gary Ruvkun of Massachusetts General Hospital in Boston have independently sequenced a gene, daf-16, which produces a that can more than double the worm's life span. The teams found that the gene encodes a transcription factor, a class of proteins that turn on other genes (Nature, vol 389, p 994; cience, vol 278, p 1319). ese worms have a choice of ong to live and daf-1 6 seems to control that by deciding which genes get turned on," says Kenyon. There are hints that the same "Methuselah" programme exists in other animals. Lab rats live longer if they eat less than their fill, and a gene like daf-16 may be involved. The gene resembles one that encodes the human transcription factor HNF-3, which switches on when levels of insulin drop in humans as a result of eating less. "It makes you think that there could be conserved genetic systems from worms to people for increasing life span when calories are restricted," comments Rudy Tanzi, a geneticist at Massachusetts General Hospital. The researchers now plan to identify the genes daf-16 switches on to repel the grim reaper. Philip Cohen, San Francisco

Long-lived daf-2 + clock mutants. Daf-2 may reduce stress and free radicals by boosting enzymes, but clock may slow down the metabolism. Such mutations may be of no use in nature because they slow down worms without increasing their resistance to parasites and infections.

Tumor Growth Reduced in Diet-Reduced Rodents

CUTTING the calories may ward off cancer, and now biologists are starting to understand why. A team in North Carolina has identified a blood protein found in large quantities in well-fed rodents which increases the growth of bladder tumours. The finding helps to explain why eating a little less can make animals-and probably people-live longer and healthier lives. The researchers hope to isolate the foods that boost production of the protein so that they can design diets for patients who face a high risk of cancer. Consuming a third fewer calories can increase a rodent's life span by 30 per cent compared with animals allowed to sate themselves at each meal. And while no one has proved that the same applies to people, some biologists are confident that this will prove to be the case. Rodents kept on a strict diet are also less likely to get cancer. Four years ago, Sandra Dunn and her colleagues at the National Institute of Environmental Health Sciences in Research Triangle Park found that animals on a diet produce less of a protein that circulates in the blood called insulin-like growth factor 1 (IGF-1). That was intriguing, says Dunn, because on the surface of many cancer cells lurks a protein called the IGF1 receptor which binds to IGF-1 To confirm whether IGF-1 plays an important role in tumour growth, the researchers fed 20 mice a carcinogen known to induce bladder cancers. All the animals were given the same essential nutrients but 10 were allowed to eat their fill of proteins and carbohydrates, while the other half had to make do with only 80 per cent of those calories. As expected, these hungry mice produced less IGF-1. Despite being exposed to carcinogen, they never developed the tumours seen in the mice allowed oz freely. And although some of the ry mice did develop a single tumour, didn't grow beyond the outside layer of the bladder. To be sure that IGF-1 was the key, a further 10 mice kept on the calorie-restricted diet were given a constant supplement of IGF-1 from a pump implanted in their skin. just like the sated mice, they developed multiple tumours. When the researchers removed tumours from both groups of hungry mice and studied how the cells grew and divided in culture, they found out why. Restoring IGF-1 to hungry animals had increased the growth rate of their tumours sixfold and reduced the rate of cell death tenfold. "IGF-1 tips the balance in favour of the tumour," says Dunn. Her team reports its results in the latest issue of Cancer Research (vol 57, p 4667). "It's a very exciting finding," says Mark Lane of the National Institute on Aging near Washington DC, who studies the effects of restricting food intake in rhesus monkeys. As well as promoting cancer, he suspects that IGF-1 may also be involved in the wear and tear of ageing. Lane points to the work of Gary Ruvkun at Massachusetts General Hospital in Boston. This summer, Ruvkun's group reported that in the nematode worm Caenorhabditis elegans, a mutation that cripples a protein similar to the IGF-1 receptor-dubbed DAF-2-increases the worm's life span. Dunn now intends to investigate whether the new insights can help ward off human cancer. If limiting IGF-1 does reduce the risk of developing a tumour, then researchers will have to analyse different foods to see which stimulate IGF-1 and which might, reduce its production. There may also be hope for people at high risk of devel oping cancer who find it hard to change their eating habits. Some drugs already in use are known to reduce the levels of IGF-1 circulating in the blood. They include the anticancer drug tamoxifen, and suramin, which is used against para sitic infections. ed a tumour Philip Cohen, San Francisco